2-acylaminopropoanol-type glucosylceramide synthase inhibitors

ABSTRACT

A compound is represented by Structural Formula (I): 
                         
or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprises a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof. A method of treating a subject in need thereof comprises administering to the subject a therapeutically effective amount of a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof. The subject has type 2 diabetes; renal hypertrophy or hyperplasia associated with diabetic nephropathy; Tay-Sachs; Gaucher&#39;s; or Fabry&#39;s disease. Methods of decreasing plasma TNF-α, lowering blood glucose levels, decreasing glycated hemoglobin levels, inhibiting glucosylceramide synthase, and lowering glycosphingolipid concentrations in a subject in need thereof respectively comprise administering to the subject a therapeutically effective amount of a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof.

RELATED APPLICATION(S)

This application is a continuation of U.S. application Ser. No.12/601,871, filed on May 6, 2010, now U.S. Pat. No. 8,304,447, issuedNov. 6, 2012, which is the U.S. National Stage of InternationalApplication No. PCT/US2008/006906, filed May 30, 2008, which designatesthe U.S., published in English, and claims the benefit of U.S.Provisional Application No. 60/932,370, filed May 31, 2007, and U.S.Provisional Application No. 60/997,846, filed on Oct. 5, 2007. Theentire teachings of the above applications are incorporated herein byreference.

BACKGROUND OF THE INVENTION

Gangliosides, such as GM1, GM2 and GM3, are glycosphingolipids (GSLs)comprised of ceramide and at least one acidic sugar. Gangliosides aregenerally found in the outer leaflet of the plasma membrane (Nojri etal., Proc. Natl. Acad. Sci. USA 83:782 (1986)). Gangliosides areinvolved in cell signaling and act as modulators of receptor activity(Yamashita et al., Proc. Natl. Acad. Sci. USA 100(6):3445 (2003)). Anumber of GSLs are derived from glucosylceramide, which is enzymaticallyformed from ceramide and UDP-glucose. The formation of glucosylceramideis catalyzed by glucosylceramide synthase.

It has been found that the level of GSLs controls a variety of cellfunctions, such as growth, differentiation, adhesion between cells orbetween cells and matrix proteins, binding of microorganisms and virusesto cells, and metastasis of tumor cells. In addition, theglucosylceramide precursor, ceramide, may cause differentiation orinhibition of cell growth and be involved in the functioning of vitaminD₃, tumor necrosis factor-α, interleukins, and apoptosis. Sphingols,precursors of ceramide, and products of ceramide catabolism have alsobeen shown to influence many cell systems, possibly by inhibitingprotein kinase C.

Defects in GSL metabolizing enzymes can cause serious disorders. Forexample, Tay-Sachs, Gaucher's, and Fabry's diseases result fromenzymatic defects in the GSL degradative pathway and the accumulation ofGSL. In particular, GM1 accumulates in the nervous system leading tomental retardation and liver enlargement. In Tay-Sachs, GM2 accumulatesin brain tissue leading to mental retardation and blindness. Theseobservations suggest that inhibitors of glycosylceramide synthase can beeffective in treating lysosomal diseases such as Tay-Sachs, Gaucher's,and Fabry's diseases. Indeed, glucosylceramide synthase inhibitors havebeen described for this purpose (see U.S. Pat. Nos. 6,569,889;6,255,336; 5,916,911; 5,302,609; 6,660,749; 6610,703; 5,472,969; and5,525,616).

Recently it has been disclosed that the interruption of the insulininduced signaling cascade may be associated with elevated levels of GM3.It has also been suggested that the cytokine tumor necrosis factor-α(TNF-α), implicated in insulin resistance, results in increasedexpression of GM3 (Tagami et al., J. Biol. Chem. 277(5):3085 (2002)).Also, it has been disclosed that mutant mice lacking GM3 synthase, andthus lacking in GM3, are protected from insulin resistance caused by ahigh-fat diet (Yamashita et al., Proc. Natl. Acad. Sc. USA 100:3445-3449(2003)). These observations suggest that inhibitors of glycosylceramidesynthase can be effective in treating diabetes. Indeed, inhibitors ofglucosylceramide synthase have been proposed for treating Type 2diabetes (see WO 2006/053043).

Therefore, agents which inhibit glucosylceramide synthesis, or reduceintracellular content of GSLs, such as GM3, have the potential to treatconditions associated with altered GSL levels and/or GSL precursorlevels. There is a need for additional agents which can act asglucosylceramide synthase inhibitors.

SUMMARY OF THE INVENTION

It has now been discovered that 2-acylaminopropoanol derivativesrepresented by Structural Formula (I) below can effectively inhibitglycosphingolipid synthesis, such as GM3 synthesis. As such, thesecompounds can be used for treating diabetes or lysosomal storagediseases, such as Tay-Sachs, Gaucher's or Fabry's disease. In addition,a number of these compounds were tested and found to significantlyinhibit glycosphingolipid synthesis in animal tissues and to have highmetabolic stability at the liver. Based upon this discovery, novel2-acylaminopropoanol derivatives, pharmaceutical compositions comprisingthe 2-acylaminopropoanol derivatives, and methods of treatment using the2-acylaminopropoanol derivatives are disclosed herein.

In one embodiment, the present invention is directed to compoundsrepresented by Structural Formula (I):

and pharmaceutically acceptable salts thereof, wherein:

R¹ is a substituted or unsubstituted aryl group;

Y is —H, a hydrolyzable group, or a substituted or unsubstituted alkylgroup.

R² and R³ are each independently —H, a substituted or unsubstitutedaliphatic group, or a substituted or unsubstituted aryl group, or R² andR³ taken together with the nitrogen atom of N(R²R³) form a substitutedor unsubstituted non-aromatic heterocyclic ring;

X is —(CR⁵R⁶)_(n)-Q-; Q is —O—, —S—, —C(O)—, —C(S)—, —C(O)O—, —C(S)O—,—C(S)S—, —C(O)NR⁷—, —NR⁷—, —NR⁷C(O)—, —NR⁷C(O)NR⁷—, —OC(O)—, —SO₃—,—SO—, —S(O)₂—, —SO₂NR⁷—, or —NR⁷SO₂—; and R⁴ is —H, a substituted orunsubstituted aliphatic group, or a substituted or unsubstituted arylgroup;

Alternatively, X is —O—, —S— or —NR⁷—; and R⁴ is a substituted orunsubstituted aliphatic group, or substituted or unsubstituted arylgroup;

Alternatively, X is —(CR⁵R⁶)_(n)—; and R⁴ is a substituted orunsubstituted cyclic alkyl group, or a substituted or unsubstitutedcyclic alkenyl group, a substituted or unsubstituted aryl group, —CN,—NCS, —NO₂ or a halogen;

Alternatively, X is a covalent bond; and R⁴ is a substituted orunsubstituted aryl group;

R⁵ and R⁶ are each independently —H, —OH, —SH, a halogen, a substitutedor unsubstituted lower alkoxy group, a substituted or unsubstitutedlower alkylthio group, or a substituted or unsubstituted lower aliphaticgroup;

n is 1, 2, 3, 4, 5 or 6;

Each R⁷ is independently —H, a substituted or unsubstituted aliphaticgroup, or a substituted or unsubstituted aryl group, or R⁷ and R⁴ takentogether with the nitrogen atom of NR⁷R⁴ form a substituted orunsubstituted non-aromatic heterocyclic group.

In another embodiment, the present invention is directed to apharmaceutical composition comprising a pharmaceutically acceptablecarrier and a compound represented by Structural Formula (1) or apharmaceutically acceptable salt thereof.

In yet another embodiment, the present invention is directed to a methodof treating a subject having type 2 diabetes, comprising administeringto the subject a therapeutically effective amount of a compoundrepresented by Structural Formula (I) or a pharmaceutically acceptablesalt thereof.

A method of treating a subject having renal hypertrophy or hyperplasiaassociated with diabetic nephropathy is also included in the invention.The method comprises administering to the subject a therapeuticallyeffective amount of a compound represented by Structural Formula (I) ora pharmaceutically acceptable salt thereof.

A method of decreasing plasma TNF-α in a subject in need thereof is alsoincluded in the present invention. The method comprises administering tothe subject a therapeutically effective amount of a compound representedby Structural Formula (I) or a pharmaceutically acceptable salt thereof

A method of lowering blood glucose levels in a subject in need thereofis also included in the present invention. The method comprisesadministering to the subject a therapeutically effective amount of acompound represented by Structural Formula (I) or a pharmaceuticallyacceptable salt thereof.

A method of decreasing glycated hemoglobin levels in a subject in needthereof is also included in the present invention. The method comprisesadministering to the subject a therapeutically effective amount of acompound represented by Structural Formula (I) or a pharmaceuticallyacceptable salt thereof.

A method of inhibiting glucosylceramide synthase or loweringglycosphingolipid concentrations in a subject in need thereof is alsoincluded in the present invention. The method comprises administering tothe subject a therapeutically effective amount of a compound representedby Structural Formula (I) or a pharmaceutically acceptable salt thereof.

A method of treating a subject with Tay-Sachs, Gaucher's or Fabry'sdisease is also included in the present invention. The method comprisesadministering to the subject a therapeutically effective amount of acompound represented by Structural Formula (I) or a pharmaceuticallyacceptable salt thereof.

Also, included in the present invention is the use of a compoundrepresented by Structural Formula (I) or a pharmaceutically acceptablesalt thereof for the manufacture of a medicament. The medicament is fortreating a subject having type 2 diabetes; for treating a subject havingrenal hypertrophy or hyperplasia associated with diabetic nephropathy;for decreasing plasma TNF-α in a subject in need thereof; for loweringblood glucose levels in a subject in need thereof; for decreasingglycated hemoglobin levels in a subject in need thereof; for inhibitingglucosylceramide synthase or lowering glycosphingolipid concentrationsin a subject in need thereof; or for treating a subject with Tay-Sachs,Gaucher's or Fabry's disease.

The compounds of the invention are inhibitors of glucosylceramidesynthesis. As such, they can be used for treating various disordersassociated with GSL metabolism, including diabetes and lysosomal storagediseases. The compounds of the invention can effectively inhibitglucosylceramide synthesis and at the same time have high metabolicstability at the liver. For example, the compounds of the invention canhave a clearance value of less than 50%, and commonly less than 30%, atthe liver relative to hepatic blood flow.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the invention is directed to a compound representedby Structural Formula (I), or a pharmaceutically acceptable saltthereof. A first set of values and preferred values for the variables inStructural Formula (I) is provided in the following paragraphs:

R¹ is a substituted or unsubstituted aryl group, such as a substitutedor unsubstituted phenyl group. Preferably, R¹ is an aryl groupoptionally substituted with one or more substituents selected fromhalogen, alkyl, haloalkyl, Ar¹, —OR³⁰, —O(haloalkyl), —SR³⁰, —NO₂, —CN,—NCS, —N(R³¹)₂, —NR³¹C(O)R³⁰, —NR³¹C(O)OR³², —N(R³¹)C(O)N(R³¹)₂,—C(O)R³⁰, —C(S)R³⁰, —C(O)OR³⁰, —OC(O)R³⁰, —C(O)N(R³¹)₂, —S(O)₂R³⁰,—SO₂N(R³¹)₂, —S(O)R³², —SO₃R³⁰, —NR³¹SO₂N(R³¹)₂, —NR³¹SO₂R³²,—V_(o)—Ar¹, —V_(o)—OR³⁰, —V_(o)—O(haloalkyl), —V_(o)—SR³⁰, —V_(o)—NO₂,—V_(o)—CN, —V_(o)—N(R³¹)₂, —V_(o)—NR³¹C(O)R³⁰, —V_(o)—NR³¹CO₂R³²,—V_(o)—N(R³¹)C(O)N(R³¹)₂, —V_(o)—C(O)R³⁰, —V_(o)—C(S)R³⁰, —V_(o)—CO₂R³⁰,—V_(o)—OC(O)R³⁰, —V_(o)—C(O)N(R³¹)₂—, —V_(o)—S(O)₂R³⁰,—V_(o)—SO₂N(R³¹)₂, —V_(o)—S(O)R³², —V_(o)—SO₃R³⁰, —V_(o)—NR³¹SO₂N(R³¹)₂,—V_(o)—NR³¹SO₂R³², —O—V_(o)—Ar¹, —O—V₁—N(R³¹)₂, —S—V_(o)—Ar¹,—S—V₁—N(R³¹)₂, —N(R³¹)—V_(o)—Ar¹, —N(R³¹)—V₁—N(R³¹)₂,—NR³¹C(O)—V_(o)—N(R³¹)₂, —NR³¹C(O)—V_(o)—Ar¹, —C(O)—V_(o)—N(R³¹)₂,—C(O)—V_(o)—Ar¹, —C(S)—V_(o)—N(R³¹)₂, —C(S)—V_(o)—Ar¹,—C(O)O—V₁—N(R³¹)₂, —C(O)O—V_(o)—Ar¹, —O—C(O)—V₁—N(R³¹)₂,—O—C(O)—V_(o)—Ar¹, —C(O)N(R³¹)—V₁—N(R³¹)₂, —C(O)N(R³¹)—V_(o)—Ar¹,—S(O)₂—V_(o)—N(R³¹)₂, —S(O)₂—V_(o)—Ar¹, —SO₂N(R³¹)—V₁—N(R³¹)₂,—SO₂N(R³¹)—V_(o)—Ar¹, —S(O)—V_(o)—N(R³¹)₂, —S(O)—V_(o)—Ar¹,—S(O)₂—O—V₁—N(R³¹)₂, —S(O)₂—O—V_(o)—Ar¹, —NR³¹SO₂—V_(o)—N(R³¹)₂,—NR³¹SO₂—V_(o)—Ar¹, —O—[CH₂]_(p)—O—, —S—[CH₂]_(p)—S—, or —[CH₂]_(q)—.More preferably, R¹ is an aryl group, such as a phenyl group, optionallysubstituted with one or more halogen, cyano, nitro, C1-C6 alkyl, C1-C6haloalkyl, —OR³⁰, —SR³⁰, —N(R³¹)₂, Ar¹, —V_(o)—OR³⁰, —V_(o)—N(R³¹)₂,—V_(o)—Ar¹, —O—V_(o)—Ar¹, —O—V₁—N(R³¹)₂, —S—V_(o)—Ar¹, —S—V₁—N(R³¹)₂,—N(R³¹)—V_(o)—Ar¹, —N(R³¹)—V₁—N(R³¹)₂, —O—[CH₂]_(p)—O—, —S—[CH₂]_(p)—S—,or —[CH₂]_(q)—. More preferably, R¹ is a phenyl group optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6alkylamino, C1-C6 dialkylamino, aryl, aryloxy, —OH, C1-C6 alkoxy,—O—[CH₂]_(p)—O—, and —[CH₂]_(q)—. Even more preferably, R¹ is a phenylgroup optionally substituted with —OH, —OCH₃, —OC₂H₅ or —O—[CH₂]_(p)—O—.Even more preferably, R¹ is

where r is 1, 2, 3 or 4, preferably 1 or 2.

Y is —H, a hydrolyzable group, or a substituted or unsubstituted alkylgroup. Examples of hydrolyzable groups include —C(O)R, —C(O)OR,—C(O)NRR′, C(S)R, —C(S)OR, —C(O)SR or —C(S)NRR′. Preferably, Y is —H,—C(O)R, —C(O)OR or —C(O)NRR′; more preferably, —H.

R² and R³ are each independently —H, a substituted or unsubstitutedaliphatic group, or a substituted or unsubstituted aryl group, or R² andR³ taken together with the nitrogen atom of N(R²R³) form a substitutedor unsubstituted non-aromatic heterocyclic ring. Preferably, R² and R³taken together with the nitrogen atom of N(R²R³) form a 5- or6-membered, optionally-substituted non-aromatic heterocyclic ring. Morepreferably, —N(R²R³) is an optionally substituted pyrrolidinyl,azetidinyl, piperidinyl, piperazinyl or morpholinyl group. Even morepreferably, —N(R²R³) is an unsubstituted pyrrolidinyl, azetidinyl,piperidinyl, piperazinyl or morpholinyl group, preferably anunsubstituted pyrrolidinyl group.

Suitable substituents for the aliphatic and aryl groups represented byR² and R³, and suitable substituents for the non-aromatic heterocyclicring represented by N(R²R³) each independently include halogen, alkyl,haloalkyl, —OR⁴⁰, —O(haloalkyl), —SR⁴⁰, —NO₂, —CN, —N(R⁴¹)₂,—NR⁴¹C(O)R⁴⁰, —NR⁴¹C(O)OR⁴², —N(R⁴¹)C(O)N(R⁴¹)₂, —C(O)R⁴⁰, —C(S)R⁴⁰,—C(O)OR⁴⁰, —OC(O)R⁴⁰, —C(O)N(R⁴¹)₂, —S(O)₂R⁴⁰, —SO₂N(R⁴¹)₂, —S(O)R⁴²,—SO₃R⁴⁰, Ar², V₂—Ar², —V₂—OR⁴⁰, —V₂—O(haloalkyl), —V₂—SR⁴⁰, —V₂—NO₂,—V₂—CN, —V₂—N(R⁴¹)₂, —V₂—NR⁴¹C(O)R⁴⁰, —V₂—NR⁴¹CO₂R⁴²,—V₂—N(R⁴¹)C(O)N(R⁴¹)₂, —V₂—C(O)R⁴⁰, —V₂—C(S)R⁴⁰, —V₂—CO₂R⁴⁰,—V₂—OC(O)R⁴⁰, —V₂—C(O)N(R⁴¹)₂—, —V₂—S(O)₂R⁴⁰, —V₂—SO₂N(R⁴¹)₂,—V₂—S(O)R⁴², —V₂—SO₃R⁴⁰, —O—V₂—Ar² and —S—V₂—Ar². Preferably, suitablesubstituents for the aliphatic and aryl groups represented by R² and R³,and suitable substituents for the non-aromatic heterocyclic ringrepresented by N(R²R³) each independently include halogen, alkyl,haloalkyl, —OR⁴⁰, —O(haloalkyl), —SR⁴⁰, —NO₂, —CN, —N(R⁴¹)₂, —C(O)R⁴⁰,—C(S)R⁴⁰, —C(O)OR⁴⁰, —OC(O)R⁴⁰, —C(O)N(R⁴¹)₂, Ar², V₂—Ar², —V₂—OR⁴⁰,—V₂—O(haloalkyl), —V₂—SR⁴⁰, —V₂—NO₂, —V₂—CN, —V₂—N(R⁴¹)₂, —V₂—C(O)R⁴⁰,—V₂—C(S)R⁴⁰, —V₂—CO₂R⁴⁰, —V₂—OC(O)R⁴⁰, —O—V₂—Ar² and —S—V₂—Ar². Morepreferably, suitable substituents for the aliphatic and aryl groupsrepresented by R² and R³, and suitable substituents for the non-aromaticheterocyclic ring represented by N(R²R³) each independently includehalogen, C1-C10 alkyl, C1-C10 haloalkyl, —O(C1-C10 alkyl), —O(phenyl),—O(C1-C10 haloalkyl), —S(C1-C10 alkyl), —S(phenyl), —S(C1-C10haloalkyl), —NO₂, —CN, —NH(C1-C10 alkyl), —N(C1-C10 alkyl)₂, —NH(C1-C10haloalkyl), —N(C1-C10 haloalkyl)₂, —NH(phenyl), —N(phenyl)₂,—C(O)(C1-C10 alkyl), —C(O)(C1-C10 haloalkyl), —C(O)(phenyl),—C(S)(C1-C10 alkyl), —C(S)(C1-C10 haloalkyl), —C(S)(phenyl),—C(O)O(C1-C10 alkyl), —C(O)O(C1-C10 haloalkyl), —C(O)O(phenyl), phenyl,—V₂-phenyl, —V₂—O-phenyl, —V₂—O(C1-C10 alkyl), —V₂—O(C1-C10 haloalkyl),—V₂—S-phenyl, —V₂—S(C1-C10 alkyl), —V₂—S(C1-C10 haloalkyl), —V₂—NO₂,—V₂—CN, —V₂—NH(C1-C10 alkyl), —V₂—N(C1-C10 alkyl)₂, —V₂—NH(C1-C10haloalkyl), —V₂—N(C1-C10 haloalkyl)₂, —V₂—NH(phenyl), —V₂—N(phenyl)₂,—V₂—C(O)(C1-C10 alkyl), —V₂—C(O)(C1-C10 haloalkyl), —V₂—C(O)(phenyl),—V₂—C(S)(C1-C10 alkyl), —V₂—C(S)(C1-C10 haloalkyl), —V₂—C(S)(phenyl),—V₂—C(O)O(C1-C10 alkyl), —V₂—C(O)O(C1-C10 haloalkyl), —V₂—C(O)O(phenyl),—V₂—OC(O)(C1-C10 alkyl), —V₂—OC(O)(C1-C10 haloalkyl), —V₂—OC(O)(phenyl),—O—V₂-phenyl and —S—V₂-phenyl. Even more preferably, suitablesubstituents for the aliphatic and aryl groups represented by R² and R³,and suitable substituents for the non-aromatic heterocyclic ringrepresented by N(R²R³) each independently include halogen, C1-C5 alkyl,C1-C5 haloalkyl, hydroxy, C1-C5 alkoxy, nitro, cyano, C1-C5alkoxycarbonyl, C1-C5 alkylcarbonyl, C1-C5 haloalkoxy, amino, C1-C5alkylamino and C1-C5 dialkylamino.

X is —(CR⁵R⁶)_(n)-Q-; Q is —O—, —S—, —C(O)—, —C(S)—, —C(O)O—, —C(S)O—,—C(S)S—, —C(O)NR⁷—, —NR⁷—, —NR⁷C(O)—, —NR⁷C(O)NR⁷—, —OC(O)—, —SO₃—,—SO—, —S(O)₂—, —SO₂NR⁷—, or —NR⁷SO₂—; and R⁴ is —H, a substituted orunsubstituted aliphatic group, or a substituted or unsubstituted arylgroup. Preferably, Q is —O—, —S—, —C(O)—, —C(S)—, —C(O)O—, —C(S)O—,—C(S)S—, —C(O)NR⁷—, —NR⁷C(O)NR⁷—, —OC(O)—, —SO₃—, —SO—, —S(O)₂—,—SO₂NR⁷— or —NR⁷SO₂—. More Preferably, Q is —O—, —S—, —C(O)—, —C(S)—,—C(O)O—, —C(S)O—, —C(S)S—, —C(O)NR⁷— or —OC(O)—. Even more preferably, Qis —O—, —S—, —C(O)— or —C(S)—.

Alternatively, X is —O—, —S— or —NR⁷—; and R⁴ is a substituted orunsubstituted aliphatic group, or substituted or unsubstituted arylgroup.

In another alternative, X is —(CR⁵R⁶)_(n)—; and R⁴ is a substituted orunsubstituted cyclic alkyl (e.g., C3-C8) group, or a substituted orunsubstituted cyclic alkenyl (C3-C8) group, a substituted orunsubstituted aryl group, —CN, —NCS, —NO₂ or a halogen.

In another alternative, X is a covalent bond; and R⁴ is a substituted orunsubstituted aryl group.

Preferably, R⁴ is an optionally substituted aliphatic, such as a loweralkyl, or aryl group. More preferably, R⁴ is an optionally substitutedaryl or lower arylalkyl group. Even more preferably, R⁴ is selected fromthe group consisting of:

wherein each of rings A-Z5 is optionally and independently substituted;and each x is independently 0 or 1, specifically x is 0. Even morepreferably, R⁴ is an optionally substituted

group. Alternatively, R⁴ is an optionally substituted phenyl group.Alternatively, R⁴ is an aryl group substituted with Ar³, such as aphenyl group substituted with Ar³. It is noted that, as shown above,rings A-Z5 can be attached to variable “X” of Structural Formula (I)through —(CH₂)_(x)— at any ring carbon of rings A-Z5 which is not at aposition bridging two aryl groups. For example, R⁴ represented by

means that R⁴ is attached to variable “X” through either ring J or ringK.

Preferred substituents for each of the aliphatic group and the arylgroup represented by R⁴, including lower alkyl, arylalkyl and ringsA-Z5, include halogen, alkyl, haloalkyl, Ar³, Ar³—Ar³, —OR⁵⁰,—O(haloalkyl), —SR⁵⁰, —NO₂, —CN, —NCS, —N(R⁵¹)₂, —NR⁵¹C(O)R⁵⁰,—NR⁵¹C(O)OR⁵², —N(R⁵¹)C(O)N(R⁵¹)₂, —C(O)R⁵⁰, —C(S)R⁵⁰, —C(O)OR⁵⁰,—OC(O)R⁵⁰, —C(O)N(R⁵¹)₂, —S(O)₂R⁵⁰, —SO₂N(R⁵¹)₂, —S(O)R⁵², —SO₃R⁵⁰,—NR⁵¹SO₂N(R⁵¹)₂, —NR⁵¹SO₂R⁵², —V₄—Ar³, —V—OR⁵⁰, —V₄—O(haloalkyl),—V₄—SR⁵⁰, —V₄—NO₂, —V₄—CN, —V₄—N(R⁵¹)₂, —V₄—NR⁵¹C(O)R⁵⁰, —V₄—NR⁵¹CO₂R⁵²,—V₄—N(R⁵¹)C(O)N(R⁵¹)₂, —V₄—C(O)R⁵⁰, —V₄—C(S)R⁵⁰, —V₄—CO₂R⁵⁰,—V₄—OC(O)R⁵⁰, —V₄—C(O)N(R⁵¹)₂—, —V₄—S(O)₂R⁵⁰, —V₄—SO₂N(R⁵¹)₂,—V₄—S(O)R⁵², —V₄—SO₃R⁵⁰, —V₄—NR⁵¹SO₂N(R⁵¹)₂, —V₄—NR⁵¹SO₂R⁵², —O—V₄—Ar³,—O—V₅—N(R⁵¹)₂, —S—V₄—Ar³, —S—V₅—N(R⁵¹)₂, —N(R⁵¹)—V₄—Ar³,—N(R⁵¹)—V₅—N(R⁵¹)₂, —NR⁵¹C(O)—V₄—N(R⁵¹)₂, —NR⁵¹C(O)—V₄—Ar³,—C(O)—V₄—N(R⁵¹)₂, —C(O)—V₄—Ar³, —C(S)—V₄—N(R⁵¹)₂, —C(S)—V₄—Ar³,—C(O)O—V₅—N(R⁵¹)₂, —C(O)O—V₄—Ar³, —O—C(O)—V₅—N(R⁵¹)₂, —O—C(O)—V₄—Ar³,—C(O)N(R⁵¹)—V₅—N(R⁵¹)₂, —C(O)N(R⁵¹)—V₄—Ar³, —S(O)₂—V₄—N(R⁵¹)₂,—S(O)₂—V₄—Ar³, —SO₂N(R⁵¹)—V₅—N(R⁵¹)₂, —SO₂N(R⁵¹)—V₄—Ar³,—S(O)—V₄—N(R⁵¹)₂, —S(O)—V₄—Ar³, —S(O)₂—O—V₅—N(R⁵¹)₂, —S(O)₂—O—V₄—Ar³,—NR⁵¹SO₂—V₄—N(R⁵¹)₂, —NR⁵¹SO₂—V₄—Ar³, —O—[CH₂]_(p′)—O—,—S—[CH₂]_(p′)—S—, and —[CH₂]_(q′)—. More preferably, substituents foreach of the aliphatic group and the aryl group represented by R⁴,including lower alkyl, arylalkyl and rings A-Z5, include halogen, C1-C10alkyl, C1-C10 haloalkyl, Ar³, Ar³—Ar³, —OR⁵⁰, —O(haloalkyl), —SR⁵⁰,—NO₂, —CN, —N(R⁵¹)₂, —NR⁵¹C(O)R⁵⁰, —C(O)R⁵⁰, —C(O)OR⁵⁰, —OC(O)R⁵⁰,—C(O)N(R⁵¹)₂, —V₄—Ar³, —V—OR⁵⁰, —V₄—O(haloalkyl), —V₄—SR⁵⁰, —V₄—NO₂,—V₄—CN, —V₄—N(R⁵¹)₂, —V₄—NR⁵¹C(O)R⁵⁰, —V₄—C(O)R⁵⁰, —V₄—CO₂R⁵⁰,—V₄—OC(O)R⁵⁰, —V₄—C(O)N(R⁵¹)₂—, —O—V₄—Ar³, —O—V₅—N(R⁵¹)₂, —S—V₄—Ar³,—S—V₅—N(R⁵¹)₂, —N(R⁵¹)—V₄—Ar³, —N(R⁵¹)—V₅—N(R⁵¹)₂, —NR⁵¹C(O)—V₄—N(R⁵¹)₂,—NR⁵¹C(O)—V₄—Ar³, —C(O)—V₄—N(R⁵¹)₂, —C(O)—V₄—Ar³, —C(O)O—V₅—N(R⁵¹)₂,—C(O)O—V₄—Ar³, —O—C(O)—V₅—N(R⁵¹)₂, —O—C(O)—V₄—Ar³,—C(O)N(R⁵¹)—V₅—N(R⁵¹)₂, —C(O)N(R⁵¹)—V₄—Ar³, —O—[CH₂]_(p′)—O— and—[CH₂]_(q′)—. More preferably, substituents for each of the aliphaticgroup and the aryl group represented by R⁴, including lower alkyl,arylalkyl and rings A-Z5, include halogen, cyano, nitro, C1-C10 alkyl,C1-C10 haloalkyl, amino, C1-C10 alkylamino, C1-C10 dialkylamino, aryl,aryloxy, hydroxy, C1-10 alkoxy, —O—[CH₂]_(p)—O— or —[CH₂]_(q)—. Evenmore preferably, substituents for each of the aliphatic group and thearyl group represented by R⁴, including lower alkyl, arylalkyl and ringsA-Z5, include halogen, cyano, amino, nitro, Ar³, C1-C6 alkyl, C1-C6haloalkyl, C1-C6 alkoxy, hydroxy and C1-C6 haloalkoxy. Even morepreferably, substituents for each of the aliphatic and aryl groupsrepresented by R⁴, including lower alkyl, arylalkyl and rings A-Z5,include —OH, —OCH₃, —OC₂H₅ and —O—[CH₂]_(p′)—O—. Preferably, phenyl ringA is optionally substituted with one or more substituents selected fromthe group consisting of halogen, cyano, nitro, C1-C10 alkyl, C1-C10haloalkyl, amino, C1-C10 alkylamino, C1-C10 dialkylamino, —OR⁵⁰, —Ar³,—V₄—Ar³, —V—OR⁵⁰, —O(C1-C10 haloalkyl), —V₄—O(C1-C10 haloalkyl),—O—V₄—Ar³, —O—[CH₂]_(p)—O— and —[CH₂]_(q)—. More preferably, phenyl ringA is optionally substituted with one or more substituents selected fromthe group consisting of halogen, cyano, nitro, C1-C10 alkyl, C1-C10haloalkyl, amino, C1-C10 alkylamino, C1-C10 dialkylamino, aryl, aryloxy,hydroxy, C1-10 alkoxy, —O—[CH₂]_(p)—O— and —[CH₂]_(q)—. Even morepreferably, phenyl ring A is optionally substituted with one or moresubstituents selected from the group consisting of —OH, —OCH₃ and—OC₂H₅. Specifically, when R⁴ is phenyl ring A, at least one of thesubstituents of ring A is at the para position.

R⁵ and R⁶ are each independently —H, —OH, —SH, a halogen, a substitutedor unsubstituted lower alkoxy group, a substituted or unsubstitutedlower alkylthio group, or a substituted or unsubstituted lower aliphaticgroup. Preferably, R⁵ and R⁶ are each independently —H; —OH; a halogen;or a lower alkoxy or lower alkyl group. More preferably, R⁵ and R⁶ areeach independently —H, —OH or a halogen. Even more preferably, R⁵ and R⁶are each independently —H.

Each R⁷ is independently —H, a substituted or unsubstituted aliphaticgroup, or a substituted or unsubstituted aryl group, or R⁷ and R⁴ takentogether with the nitrogen atom of NR⁷R⁴ form a substituted orunsubstituted non-aromatic heterocyclic group. Preferably, each R⁷ isindependently —H, an aliphatic group or phenyl. Even more preferably,each R⁷ is independently —H or C1-C6 alkyl.

Each n is independently 1, 2, 3, 4, 5 or 6. Preferably, each n isindependently 1, 2, 3 or 4. Alternatively, each n is independently 2, 3,4 or 5.

Each p is independently 1, 2, 3 or 4, preferably 1 or 2.

Each q is independently 3, 4, 5 or 6, preferably 3 or 4.

Each p′ is independently 1, 2, 3 or 4, preferably 1 or 2.

Each q′ is independently 3, 4, 5 or 6, preferably 3 or 4.

Each V_(o) is independently a C1-C10 alkylene group, preferably C1-C4alkylene group.

Each V₁ is independently a C2-C10 alkylene group, specifically C2-C4alkylene group.

Each V₂ is independently a C1-C4 alkylene group.

Each V₄ is independently a C1-C10 alkylene group, preferably a C1-C4alkylene group.

Each V₅ is independently a C2-C10 alkylene group, preferably a C2-C4alkylene group.

Each Ar¹ is an aryl group optionally and independently substituted withone or more substituents selected from the group consisting of halogen,alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy,haloalkoxy and haloalkyl. Preferably, Ar¹ is an aryl group eachoptionally substituted with one or more substituents selected from thegroup consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy,C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl. Morepreferably, Ar¹ is a phenyl group each optionally substituted with oneor more substituents selected from the group consisting of halogen,C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy,nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6alkylcarbonyl and C1-C6 haloalkyl.

Each Ar² is an aryl group optionally and independently substituted withone or more substituents selected from the group consisting of halogen,C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano, C1-C6alkoxycarbonyl, C1-C6 alkylcarbonyl, C1-C6 haloalkoxy, amino, C1-C6alkylamino and C1-C6 dialkylamino.

Each Ar³ is independently an aryl group, such as phenyl, each optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy,nitro, cyano, hydroxy, haloalkoxy and haloalkyl. Preferably, Ar³ isindependently an aryl group each optionally substituted with one or moresubstituents selected from the group consisting of halogen, C1-C10alkyl, C1-C10 haloalkyl, hydroxy, C1-C10 alkoxy, nitro, cyano, C1-C10alkoxycarbonyl, C1-C10 alkylcarbonyl, C1-C10 haloalkoxy, amino, C1-C10alkylamino and C1-C10 dialkylamino. Even more preferably, Ar³ isindependently an aryl group each optionally substituted with one or moresubstituents selected from the group consisting of halogen, C1-C4 alkyl,C1-C4 haloalkyl, hydroxy, C1-C4 alkoxy, nitro, cyano, C1-C4alkoxycarbonyl, C1-C4 alkylcarbonyl, C1-C4 haloalkoxy, amino, C1-C4alkylamino and C1-C4 dialkylamino

Each R³⁰ is independently hydrogen; an aryl group optionally substitutedwith one or more substituents selected from the group consisting ofhalogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano,hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; or analkyl group optionally substituted with one or more substituentsselected from the group consisting of halogen, amino, alkylamino,dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyland alkylcarbonyl. Preferably, each R³⁰ is independently hydrogen; anaryl group optionally substituted with one or more substituents selectedfrom the group consisting of halogen, C1-C6 alkyl, amino, C1-C6alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy,C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6haloalkyl; or an C1-C10 alkyl group optionally substituted with one ormore substituents selected from the group consisting of halogen, amino,C1-C6 alkylamino, C1-C1 dialkylamino, C1-C6 alkoxy, nitro, cyano,hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl and C1-C6 alkylcarbonyl.More preferably, each R³⁰ is independently hydrogen; a phenyl groupoptionally substituted with one or more substituents selected from thegroup consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy,C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; or anC1-C10 alkyl group optionally substituted with one or more substituentsselected from the group consisting of halogen, amino, C1-C6 alkylamino,C1-C1 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6haloalkoxy, C1-C6 alkoxycarbonyl and C1-C6 alkylcarbonyl.

Each R³¹ is independently R³⁰, —CO₂R³⁰, —SO₂R³⁰ or —C(O)R³⁰; or —N(R³¹)₂taken together is an optionally substituted non-aromatic heterocyclicgroup. Preferably, each R³¹ is independently R³⁰, or —N(R³¹)₂ is anoptionally substituted non-aromatic heterocyclic group.

Each R³² is independently an aryl group optionally substituted with oneor more substituents selected from the group consisting of halogen,alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy,haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; or an alkylgroup optionally substituted with one or more substituents selected fromthe group consisting of halogen, amino, alkylamino, dialkylamino,alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl andalkylcarbonyl. Preferably, each R³² is independently an aryl groupoptionally substituted with one or more substituents selected from thegroup consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy,C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; or aC1-C10 alkyl group optionally substituted with one or more substituentsselected from the group consisting of halogen, amino, C1-C6 alkylamino,C1-C1 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6haloalkoxy, C1-C6 alkoxycarbonyl and C1-C6 alkylcarbonyl. Morepreferably, each R³² is independently a phenyl group optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy andC1-C6 haloalkyl; or a C1-C10 alkyl group optionally substituted with oneor more substituents selected from the group consisting of halogen,amino, C1-C6 alkylamino, C1-C1 dialkylamino, C1-C6 alkoxy, nitro, cyano,hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl and C1-C6 alkylcarbonyl.

Each R⁴⁰ is independently hydrogen; an aryl group, such as a phenylgroup, optionally substituted with one or more substituents selectedfrom the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl,hydroxy, C1-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl, C1-C6alkylcarbonyl, C1-C6 haloalkoxy, amino, C1-C6 alkylamino and C1-C6dialkylamino; or a C1-C10 alkyl group optionally substituted with one ormore substituents selected from the group consisting of halogen, C1-C6haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl,C1-C6 alkylcarbonyl, C1-C6 haloalkoxy, amino, C1-C6 alkylamino and C1-C6dialkylamino.

Each R⁴¹ is independently R⁴⁰, —CO₂R⁴⁰, —SO₂R⁴⁰ or —C(O)R⁴⁰; or —N(R⁴¹)₂taken together is an optionally substituted non-aromatic heterocyclicgroup.

Each R⁴² is independently an aryl group, such as a phenyl group,optionally substituted with one or more substituents selected from thegroup consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy,C1-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl,C1-C6 haloalkoxy, amino, C1-C6 alkylamino and C1-C6 dialkylamino; or aC1-C10 alkyl group optionally substituted with one or more substituentsselected from the group consisting of halogen, C1-C6 haloalkyl, hydroxy,C1-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl,C1-C6 haloalkoxy, amino, C1-C6 alkylamino and C1-C6 dialkylamino.

Each R⁵⁰ is independently hydrogen; an aryl group optionally substitutedwith one or more substituents selected from the group consisting ofhalogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano,hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; or analkyl group optionally substituted with one or more substituentsselected from the group consisting of halogen, amino, alkylamino,dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl,alkylcarbonyl and haloalkyl. Preferably, each R⁵⁰ is independentlyhydrogen; an aryl group, such as a phenyl group, optionally substitutedwith one or more substituents selected from the group consisting ofhalogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, nitro,cyano, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl, C1-C6 haloalkoxy,amino, C1-C6 alkylamino and C1-C6 dialkylamino; or a C1-C10 alkyl groupoptionally substituted with one or more substituents selected from thegroup consisting of halogen, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy,nitro, cyano, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl, C1-C6haloalkoxy, amino, C1-C6 alkylamino and C1-C6 dialkylamino.

Each R⁵¹ is independently R⁵⁰, —CO₂R⁵⁰, —SO₂R⁵⁰ or —C(O)R⁵⁰, or —N(R⁵¹)₂taken together is an optionally substituted non-aromatic heterocyclicgroup. Preferably, each R⁵¹ is independently R⁵⁰, or —N(R³¹)₂ is anoptionally substituted non-aromatic heterocyclic group.

Each R⁵² is independently an aryl group optionally substituted with oneor two substituents selected from the group consisting of halogen,alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy,haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; or an alkylgroup optionally substituted with one or more substituents selected fromthe group consisting of halogen, amino, alkylamino, dialkylamino,alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyland haloalkyl. Preferably, each R⁵² is independently an aryl group, suchas a phenyl group, optionally substituted with one or more substituentsselected from the group consisting of halogen, C1-C6 alkyl, C1-C6haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl,C1-C6 alkylcarbonyl, C1-C6 haloalkoxy, amino, C1-C6 alkylamino and C1-C6dialkylamino; or a C1-C10 alkyl group optionally substituted with one ormore substituents selected from the group consisting of halogen, C1-C6haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl,C1-C6 alkylcarbonyl, C1-C6 haloalkoxy, amino, C1-C6 alkylamino and C1-C6dialkylamino.

R and R′ are each independently —H; a lower aliphatic group optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, —OH, —CN, —NCS, —NO₂, —NH₂, lower alkoxy, lowerhaloalkoxy and aryl; or an aryl group optionally substituted with one ormore substituents selected from the group consisting of halogen, —OH,—CN, —NCS, —NO₂, —NH₂, lower alkoxy, lower haloalkoxy, lower aliphaticgroup and lower haloaliphatic group; or R and R′ taken together with thenitrogen atom of NRR′ form a non-aromatic heterocyclic ring optionallysubstituted with one or more substituents selected from the groupconsisting of: halogen; —OH; —CN; —NCS; —NO₂; —NH₂; lower alkoxy; lowerhaloalkoxy; lower aliphatic group optionally substituted with one ormore substituents selected from the group consisting of halogen, —OH,—CN, —NCS, —NO₂, —NH₂, lower alkoxy, lower haloalkoxy and aryl; and arylgroup optionally substituted with one or more substituents selected fromthe group consisting of halogen, —OH, —CN, —NCS, —NO₂, —NH₂, loweralkoxy, lower haloalkoxy, lower aliphatic group and lower haloaliphaticgroup. Preferably, R and R′ are each independently —H; a lower aliphaticgroup; a lower aliphatic group substituted with phenyl; or an arylgroup. More preferably, R and R′ are each independently —H, C1-C4 alkyl,phenyl or benzyl.

A second set of values for the variables in Structural Formula (I) isprovided in the following paragraphs:

Y is —H, —C(O)R, —C(O)OR or —C(O)NRR′, preferably —H.

R¹ is an aryl group optionally substituted with one or more substituentsselected from the group consisting of halogen, alkyl, haloalkyl, Ar¹,—OR³⁰, —O(haloalkyl), —SR³⁰, —NO₂, —CN, —NCS, —N(R³¹)₂, —NR³¹C(O)R³⁰,—NR³¹C(O)OR³², —N(R³¹)C(O)N(R³¹)₂, —C(O)R³⁰, —C(S)R³⁰, —C(O)OR³⁰,—OC(O)R³⁰, —C(O)N(R³¹)₂, —S(O)₂R³⁰, —SO₂N(R³¹)₂, —S(O)R³², —SO₃R³⁰,—NR³¹SO₂N(R³¹)₂, —NR³¹SO₂R³², —V_(o)—Ar¹, —V_(o)—OR³⁰,—V_(o)—O(haloalkyl), —V_(o)—SR³⁰, —V_(o)—NO₂, —V_(o)—CN, —V_(o)—N(R³¹)₂,—V_(o)—NR³¹C(O)R³⁰, —V_(o)—NR³¹CO₂R³², —V_(o)—N(R³¹)C(O)N(R³¹)₂,—V_(o)—C(O)R³⁰, —V_(o)—C(S)R³⁰, —V_(o)—CO₂R³⁰, —V_(o)—OC(O)R³⁰,—V_(o)—C(O)N(R³¹)₂—, —V_(o)—S(O)₂R³⁰, —V_(o)—SO₂N(R³¹)₂, —V_(o)—S(O)R³²,—V_(o)—SO₃R³⁰, —V_(o)—NR³¹SO₂N(R³¹)₂, —V_(o)—NR³¹SO₂R³², —O—V_(o)—Ar¹,—O—V₁—N(R³¹)₂, —S—V_(o)—Ar¹, —S—V₁—N(R³¹)₂, —N(R³¹)—V_(o)—Ar¹,—N(R³¹)—V₁—N(R³¹)₂, —NR³¹C(O)—V_(o)—N(R³¹)₂, —NR³¹C(O)—V_(o)—Ar¹,—C(O)—V_(o)—N(R³¹)₂, —C(O)—V_(o)—Ar¹, —C(S)—V_(o)—N(R³¹)₂,—C(S)—V_(o)—Ar¹, —C(O)O—V₁—N(R³¹)₂, —C(O)O—V_(o)—Ar¹,—O—C(O)—V₁—N(R³¹)₂, —O—C(O)—V_(o)—Ar¹, —C(O)N(R³¹)—V₁—N(R³¹)₂,—C(O)N(R³¹)—V_(o)—Ar¹, —S(O)₂—V_(o)—N(R³¹)₂, —S(O)₂—V_(o)—Ar¹,—SO₂N(R³¹)—V₁—N(R³¹)₂, —SO₂N(R³¹)—V_(o)—Ar¹, —S(O)—V_(o)—N(R³¹)₂,—S(O)—V_(o)—Ar¹, —S(O)₂—O—V₁—N(R³¹)₂, —S(O)₂—O—V_(o)—Ar¹,—NR³¹SO₂—V_(o)—N(R³¹)₂, —NR³¹SO₂—V_(o)—Ar¹, —O—[CH₂]_(p)—O—,—S—[CH₂]_(p)—S— and —[CH₂]_(q)—.

Values and preferred values for the remainder of the variables ofStructural Formula (I) are each independently as described above for thefirst set of values.

A third set of values for the variables in Structural Formula (I) isprovided in the following four paragraphs.

Y is —H, —C(O)R, —C(O)OR or —C(O)NRR′, preferably —H.

R¹ is an aryl group optionally substituted with one or more substituentsselected from the group consisting of halogen, alkyl, haloalkyl, Ar¹,—OR³⁰, —O(haloalkyl), —SR³⁰, —NO₂, —CN, —NCS, —N(R³¹)₂, —NR³¹C(O)R³⁰,—NR³¹C(O)OR³², —N(R³¹)C(O)N(R³¹)₂, —C(O)R³⁰, —C(S)R³⁰, —C(O)OR³⁰,—OC(O)R³⁰, —C(O)N(R³¹)₂, —S(O)₂R³⁰, —SO₂N(R³¹)₂, —S(O)R³², —SO₃R³⁰,—NR³¹SO₂N(R³¹)₂, —NR³¹SO₂R³², —V_(o)—Ar¹, —V_(o)—OR³⁰,—V_(o)—O(haloalkyl), —V_(o)—SR³⁰, —V_(o)—NO₂, —V_(o)—CN, —V_(o)—N(R³¹)₂,—V_(o)—NR³¹C(O)R³⁰, —V_(o)—NR³¹CO₂R³², —V_(o)—N(R³¹)C(O)N(R³¹)₂,—V_(o)—C(O)R³⁰, —V_(o)—C(S)R³⁰, —V_(o)—CO₂R³⁰, —V_(o)—OC(O)R³⁰,—V_(o)—C(O)N(R³¹)₂—, —V_(o)—S(O)₂R³⁰, —V_(o)—SO₂N(R³¹)₂, —V_(o)—S(O)R³²,—V_(o)—SO₃R³⁰, —V_(o)—NR³¹SO₂N(R³¹)₂, —V_(o)—NR³¹SO₂R³², —O—V_(o)—Ar¹,—O—V₁—N(R³¹)₂, —S—V_(o)—Ar¹, —S—V₁—N(R³¹)₂, —N(R³¹)—V_(o)—Ar¹,—N(R³¹)—V₁—N(R³¹)₂, —NR³¹C(O)—V_(o)—N(R³¹)₂, —NR³¹C(O)—V_(o)—Ar¹,—C(O)—V_(o)—N(R³¹)₂, —C(O)—V_(o)—Ar¹, —C(S)—V_(o)—N(R³¹)₂,—C(S)—V_(o)—Ar¹, —C(O)O—V₁—N(R³¹)₂, —C(O)O—V_(o)—Ar¹,—O—C(O)—V₁—N(R³¹)₂, —O—C(O)—V_(o)—Ar¹, —C(O)N(R³¹)—V₁—N(R³¹)₂,—C(O)N(R³¹)—V_(o)—Ar¹, —S(O)₂—V_(o)—N(R³¹)₂, —S(O)₂—V_(o)—Ar¹,—SO₂N(R³¹)—V₁—N(R³¹)₂, —SO₂N(R³¹)—V_(o)—Ar¹, —S(O)—V_(o)—N(R³¹)₂,—S(O)—V_(o)—Ar¹, —S(O)₂—O—V₁—N(R³¹)₂, —S(O)₂—O—V_(o)—Ar¹,—NR³¹SO₂—V_(o)—N(R³¹)₂, —NR³¹SO₂—V_(o)—Ar¹, —O—[CH₂]_(p)—O—,—S—[CH₂]_(p)—S— and —[CH₂]_(q)—.

R² and R³ taken together with the nitrogen atom of N(R²R³) form a 5- or6-membered, optionally-substituted non-aromatic heterocyclic ring.Examples of suitable substituents for the non-aromatic heterocyclic ringrepresented by —NR²R³ are as described in the first set of values forStructural Formula (I).

Values and preferred values for the remainder of the variables ofStructural Formula (I) are as described above for the first set ofvalues.

A fourth set of values for the variables in Structural Formula (I) isprovided in the following paragraphs:

Y is —H, —C(O)R, —C(O)OR or —C(O)NRR′, preferably —H.

R¹ is an aryl group optionally substituted with one or more substituentsselected from the group consisting of halogen, alkyl, haloalkyl, Ar¹,—OR³⁰, —O(haloalkyl), —SR³⁰, —NO₂, —CN, —NCS, —N(R³¹)₂, —NR³¹C(O)R³⁰,—NR³¹C(O)OR³², —N(R³¹)C(O)N(R³¹)₂, —C(O)R³⁰, —C(S)R³⁰, —C(O)OR³⁰,—OC(O)R³⁰, —C(O)N(R³¹)₂, —S(O)₂R³⁰, —SO₂N(R³¹)₂, —S(O)R³², —SO₃R³⁰,—NR³¹SO₂N(R³¹)₂, —NR³¹SO₂R³², —V_(o)—Ar¹, —V_(o)—OR³⁰,—V_(o)—O(haloalkyl), —V_(o)—SR³⁰, —V_(o)—NO₂, —V_(o)—CN, —V_(o)—N(R³¹)₂,—V_(o)—NR³¹C(O)R³⁰, —V_(o)—NR³¹CO₂R³², —V_(o)—N(R³¹)C(O)N(R³¹)₂,—V_(o)—C(O)R³⁰, —V_(o)—C(S)R³⁰, —V_(o)—CO₂R³⁰, —V_(o)—OC(O)R³⁰,—V_(o)—C(O)N(R³¹)₂—, —V_(o)—S(O)₂R³⁰, —V_(o)—SO₂N(R³¹)₂, —V_(o)—S(O)R³²,—V_(o)—SO₃R³⁰, —V_(o)—NR³¹SO₂N(R³¹)₂, —V_(o)—NR³¹SO₂R³², —O—V_(o)—Ar¹,—O—V₁—N(R³¹)₂, —S—V_(o)—Ar¹, —S—V₁—N(R³¹)₂, —N(R³¹)—V_(o)—Ar¹,—N(R³¹)—V₁—N(R³¹)₂, —NR³¹C(O)—V_(o)—N(R³¹)₂, —NR³¹C(O)—V_(o)—Ar¹,—C(O)—V_(o)—N(R³¹)₂, —C(O)—V_(o)—Ar¹, —C(S)—V_(o)—N(R³¹)₂,—C(S)—V_(o)—Ar¹, —C(O)O—V₁—N(R³¹)₂, —C(O)O—V_(o)—Ar¹,—O—C(O)—V₁—N(R³¹)₂, —O—C(O)—V_(o)—Ar¹, —C(O)N(R³¹)—V₁—N(R³¹)₂,—C(O)N(R³¹)—V_(o)—Ar¹, —S(O)₂—V_(o)—N(R³¹)₂, —S(O)₂—V_(o)—Ar¹,—SO₂N(R³¹)—V₁—N(R³¹)₂, —SO₂N(R³¹)—V_(o)—Ar¹, —S(O)—V_(o)—N(R³¹)₂,—S(O)—V_(o)—Ar¹, —S(O)₂—O—V₁—N(R³¹)₂, —S(O)₂—O—V_(o)—Ar¹,—NR³¹SO₂—V_(o)—N(R³¹)₂, —NR³¹SO₂—V_(o)—Ar¹, —O—[CH₂]_(p)—O—,—S—[CH₂]_(p)—S— and —[CH₂]_(q)—.

R² and R³ taken together with the nitrogen atom of N(R²R³) form a 5- or6-membered, optionally-substituted non-aromatic heterocyclic ring.

R⁵ and R⁶ are each independently —H, —OH, a halogen, a lower alkoxygroup or a lower alkyl group.

Values and preferred values of the remainder of the variables ofStructural Formula (I) are each independently as described above for thefirst set of values.

A fifth set of values for the variables in Structural Formula (I) isprovided in the following paragraphs:

Y is —H, —C(O)R, —C(O)OR or —C(O)NRR′, preferably —H.

R¹ is an aryl group optionally substituted with one or more substituentsselected from the group consisting of halogen, alkyl, haloalkyl, Ar¹,—OR³⁰, —O(haloalkyl), —SR³⁰, —NO₂, —CN, —NCS, —N(R³¹)₂, —NR³¹C(O)R³⁰,—NR³¹C(O)OR³², —N(R³¹)C(O)N(R³¹)₂, —C(O)R³⁰, —C(S)R³⁰, —C(O)OR³⁰,—OC(O)R³⁰, —C(O)N(R³¹)₂, —S(O)₂R³⁰, —SO₂N(R³¹)₂, —S(O)R³², —SO₃R³⁰,—NR³¹SO₂N(R³¹)₂, —NR³¹SO₂R³², —V_(o)—Ar¹, —V_(o)—OR³⁰,—V_(o)—O(haloalkyl), —V_(o)—SR³⁰, —V_(o)—NO₂, —V_(o)—CN, —V_(o)—N(R³¹)₂,—V_(o)—NR³¹C(O)R³⁰, —V_(o)—NR³¹CO₂R³², —V_(o)—N(R³¹)C(O)N(R³¹)₂,—V_(o)—C(O)R³⁰, —V_(o)—C(S)R³⁰, —V_(o)—CO₂R³⁰, —V_(o)—OC(O)R³⁰,—V_(o)—C(O)N(R³¹)₂—, —V_(o)—S(O)₂R³⁰, —V_(o)—SO₂N(R³¹)₂, —V_(o)—S(O)R³²,—V_(o)—SO₃R³⁰, —V_(o)—NR³¹SO₂N(R³¹)₂, —V_(o)—NR³¹SO₂R³², —O—V_(o)—Ar¹,—O—V₁—N(R³¹)₂, —S—V_(o)—Ar¹, —S—V₁—N(R³¹)₂, —N(R³¹)—V_(o)—Ar¹,—N(R³¹)—V₁—N(R³¹)₂, —NR³¹C(O)—V_(o)—N(R³¹)₂, —NR³¹C(O)—V_(o)—Ar¹,—C(O)—V_(o)—N(R³¹)₂, —C(O)—V_(o)—Ar¹, —C(S)—V_(o)—N(R³¹)₂,—C(S)—V_(o)—Ar¹, —C(O)O—V₁—N(R³¹)₂, —C(O)O—V_(o)—Ar¹,—O—C(O)—V₁—N(R³¹)₂, —O—C(O)—V_(o)—Ar¹, —C(O)N(R³¹)—V₁—N(R³¹)₂,—C(O)N(R³¹)—V_(o)—Ar¹, —S(O)₂—V_(o)—N(R³¹)₂, —S(O)₂—V_(o)—Ar¹,—SO₂N(R³¹)—V₁—N(R³¹)₂, —SO₂N(R³¹)—V_(o)—Ar¹, —S(O)—V_(o)—N(R³¹)₂,—S(O)—V_(o)—Ar¹, —S(O)₂—O—V₁—N(R³¹)₂, —S(O)₂—O—V_(o)—Ar¹,—NR³¹SO₂—V_(o)—N(R³¹)₂, —NR³¹SO₂—V_(o)—Ar¹, —O—[CH₂]_(p)—O—,—S—[CH₂]_(p)—S— and —[CH₂]_(q)—.

R² and R³ taken together with the nitrogen atom of N(R²R³) form a 5- or6-membered, optionally-substituted non-aromatic heterocyclic ring.

R⁴ is an aliphatic or aryl group each optionally substituted with one ormore substituents. Examples of suitable substituents are as describedabove for the first set of values.

R⁵ and R⁶ are each independently —H, —OH, a halogen, a lower alkoxygroup or a lower alkyl group.

Values and preferred values of the remainder of the variables ofStructural Formula (I) are each independently as described above for thefirst set of values.

A sixth set of values for the variables in Structural Formula (I) isprovided in the following paragraphs:

Y is —H, —C(O)R, —C(O)OR or —C(O)NRR′, preferably —H.

R¹ is an aryl group optionally substituted with one or more substituentsselected from the group consisting of halogen, alkyl, haloalkyl, Ar¹,—OR³⁰, —O(haloalkyl), —SR³⁰, —NO₂, —CN, —NCS, —N(R³¹)₂, —NR³¹C(O)R³⁰,—NR³¹C(O)OR³², —N(R³¹)C(O)N(R³¹)₂, —C(O)R³⁰, —C(S)R³⁰, —C(O)OR³⁰,—OC(O)R³⁰, —C(O)N(R³¹)₂, —S(O)₂R³⁰, —SO₂N(R³¹)₂, —S(O)R³², —SO₃R³⁰,—NR³¹SO₂N(R³¹)₂, —NR³¹SO₂R³², —V_(o)—Ar¹, —V_(o)—OR³⁰,—V_(o)—O(haloalkyl), —V_(o)—SR³⁰, —V_(o)—NO₂, —V_(o)—CN, —V_(o)—N(R³¹)₂,—V_(o)—NR³¹C(O)R³⁰, —V_(o)—NR³¹CO₂R³², —V_(o)—N(R³¹)C(O)N(R³¹)₂,—V_(o)—C(O)R³⁰, —V_(o)—C(S)R³⁰, —V_(o)—CO₂R³⁰, —V_(o)—OC(O)R³⁰,—V_(o)—C(O)N(R³¹)₂—, —V_(o)—S(O)₂R³⁰, —V_(o)—SO₂N(R³¹)₂, —V_(o)—S(O)R³²,—V_(o)—SO₃R³⁰, —V_(o)—NR³¹SO₂N(R³¹)₂, —V_(o)—NR³¹SO₂R³², —O—V_(o)—Ar¹,—O—V₁—N(R³¹)₂, —S—V_(o)—Ar¹, —S—V₁—N(R³¹)₂, —N(R³¹)—V_(o)—Ar¹,—N(R³¹)—V₁—N(R³¹)₂, —NR³¹C(O)—V_(o)—N(R³¹)₂, —NR³¹C(O)—V_(o)—Ar¹,—C(O)—V_(o)—N(R³¹)₂, —C(O)—V_(o)—Ar¹, —C(S)—V_(o)—N(R³¹)₂,—C(S)—V_(o)—Ar¹, —C(O)O—V₁—N(R³¹)₂, —C(O)O—V_(o)—Ar¹,—O—C(O)—V₁—N(R³¹)₂, —O—C(O)—V_(o)—Ar¹, —C(O)N(R³¹)—V₁—N(R³¹)₂,—C(O)N(R³¹)—V_(o)—Ar¹, —S(O)₂—V_(o)—N(R³¹)₂, —S(O)₂—V_(o)—Ar¹,—SO₂N(R³¹)—V₁—N(R³¹)₂, —SO₂N(R³¹)—V_(o)—Ar¹, —S(O)—V_(o)—N(R³¹)₂,—S(O)—V_(o)—Ar¹, —S(O)₂—O—V₁—N(R³¹)₂, —S(O)₂—O—V_(o)—Ar¹,—NR³¹SO₂—V_(o)—N(R³¹)₂, —NR³¹SO₂—V_(o)—Ar¹, —O—[CH₂]_(p)—O—,—S—[CH₂]_(p)—S— and —[CH₂]_(q)—.

R² and R³ taken together with the nitrogen atom of N(R²R³) form a 5- or6-membered, optionally-substituted non-aromatic heterocyclic ring.

R⁴ is an optionally substituted cyclic alkyl group, or an optionallysubstituted cyclic alkenyl group, an optionally substituted aryl group,—CN, —NCS, —NO₂ or a halogen. Examples of suitable substituents are asdescribed above for the first set.

R⁵ and R⁶ are each independently —H, —OH, a halogen, a lower alkoxygroup or a lower alkyl group.

Values and preferred values of the remainder of the variables ofStructural Formula (I) are each independently as described above for thefirst set of values.

A seventh set of values and preferred values for the variables inStructural Formula (I) is provided in the following paragraphs:

Values and preferred values of R¹, Y, R², R³, R⁵ and R⁶ are eachindependently as described above for the sixth set.

R⁴ is an optionally substituted cyclic alkyl group, or an optionallysubstituted cyclic alkenyl group, or an optionally substituted arylgroup, specifically optionally substituted aryl group. Examples ofsuitable substituents are as described above for the first set.

Values and preferred values of the remainder of the variables ofStructural Formula (I) are each independently as described above for thefirst set of values.

In a second embodiment, the compound of the invention is represented byStructural Formula (II), (III), (IV), (V), (VI), (VII) or (VIII):

or a pharmaceutically acceptable salt thereof. A first set of values forthe variables of Structural Formulas (II)-(VIII) is provided in thefollowing paragraphs:

R¹ is a phenyl group optionally substituted with one or moresubstituents selected from the group consisting of halogen, cyano,nitro, C1-C6 alkyl, C1-C6 haloalkyl, —OR³⁰, —SR³⁰, —N(R³¹)₂, Ar¹,—V_(o)—OR³⁰, —V_(o)—N(R³¹)₂, —V_(o)—Ar¹, —O—V_(o)—Ar¹, —O—V₁—N(R³¹)₂,—S—V_(o)—Ar¹, —S—V₁—N(R³¹)₂, —N(R³¹)—V_(o)—Ar¹, —N(R³¹)—V₁—N(R³¹)₂,—O—[CH₂]_(p)—O—, —S—[CH₂]_(p)—S— and —[CH₂]_(q)—. Preferably, R¹ is aphenyl group optionally substituted with one or more substituentsselected from the group consisting of halogen, cyano, nitro, C1-C6alkyl, C1-C6 haloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, aryl,aryloxy, —OH, C1-C6 alkoxy, —O—[CH₂]_(p)—O— and —[CH₂]_(q)—.

Ar¹ is an aryl group each optionally substituted with one or moresubstituents selected from the group consisting of halogen, C1-C6 alkyl,amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano,hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl andC1-C6 haloalkyl. Preferably, Ar¹ is a phenyl group each optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy,C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl.

R³⁰ is independently hydrogen; an aryl group optionally substituted withone or more substituents selected from the group consisting of halogen,C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy,nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6alkylcarbonyl and C1-C6 haloalkyl; or a C1-C10 alkyl group optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino,C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl. Preferably, R³⁰is independently hydrogen; a phenyl group optionally substituted withone or more substituents selected from the group consisting of halogen,C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy,nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6alkylcarbonyl and C1-C6 haloalkyl; or a C1-C10 alkyl group optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino,C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl.

Each R³¹ is independently R³⁰, or —N(R³¹)₂ is an optionally substitutednon-aromatic heterocyclic group. Examples of suitable substituents areas described above in the first set of values for Structural Formula(I).

R² and R³ taken together with the nitrogen atom of N(R²R³) form a 5- or6-membered, optionally-substituted non-aromatic heterocyclic ring.Examples of suitable substituents for the non-aromatic heterocyclic ringrepresented by —NR²R³ are as described above in the first set of valuesfor Structural Formula (I).

R⁴ is an aliphatic or aryl group each optionally substituted with one ormore substituents described above in the first set of values forStructural Formula (I).

R⁵ and R⁶ for Structural Formulas (II), (III) and (V) are eachindependently —H, —OH, a halogen, a lower alkoxy group or a lower alkylgroup.

For Structural Formula (VIII), R⁷ is —H or C1-C6 alkyl, preferably —H.

Values and preferred values of the remainder of the variables ofStructural Formulas (II)-(VIII) are each independently as describedabove in the first set of values for Structural Formula (I).

A second set of values for the variables in Structural Formulas(II)-(VIII) is provided in the following paragraphs:

R¹ is a phenyl group optionally substituted with one or moresubstituents selected from the group consisting of halogen, cyano,nitro, C1-C6 alkyl, C1-C6 haloalkyl, —OR³⁰, —SR³⁰, —N(R³¹)₂, Ar¹,—V_(o)—OR³⁰, —V_(o)—N(R³¹)₂, —V_(o)—Ar¹, —O—V₁—Ar¹, —O—V₁—N(R³¹)₂,—S—V_(o)—Ar¹, —S—V₁—N(R³¹)₂, —N(R³¹)—V_(o)—Ar¹, —N(R³¹)—V₁—N(R³¹)₂,—O—[CH₂]_(p)—O—, —S—[CH₂]_(p)—S—, or —[CH₂]_(q)—. Preferably, R¹ is aphenyl group optionally substituted with one or more substituentsselected from the group consisting of halogen, cyano, nitro, C1-C6alkyl, C1-C6 haloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, aryl,aryloxy, —OH, C1-C6 alkoxy, —O—[CH₂]_(p)—O— and —[CH₂]_(q)—.

Ar¹ is an aryl group each optionally substituted with one or moresubstituents selected from the group consisting of halogen, C1-C6 alkyl,amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano,hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl andC1-C6 haloalkyl. Preferably, Ar¹ is a phenyl group each optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy,C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl.

R³⁰ is independently hydrogen; an aryl group optionally substituted withone or more substituents selected from the group consisting of halogen,C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy,nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6alkylcarbonyl and C1-C6 haloalkyl; or a C1-C10 alkyl group optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino,C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl. Preferably, R³⁰is independently hydrogen; a phenyl group optionally substituted withone or more substituents selected from the group consisting of halogen,C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy,nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6alkylcarbonyl and C1-C6 haloalkyl; or a C1-C10 alkyl group optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino,C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl.

Each R³¹ is independently R³⁰, or —N(R³¹)₂ is an optionally substitutednon-aromatic heterocyclic group.

—N(R²R³) is a pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl ormorpholinyl group optionally substituted with one or more substituentsselected from the group consisting of halogen, C1-C5 alkyl, C1-C5haloalkyl, hydroxyl, C1-C5 alkoxy, nitro, cyano, C1-C5 alkoxycarbonyl,C1-C5 alkylcarbonyl or C1-C5 haloalkoxy, amino, C1-C5 alkylamino andC1-C5 dialkylamino

R⁴ is an aliphatic or aryl group each optionally substituted with one ormore substituents. Examples of suitable substituents are described abovein the first set of values for Structural Formula (I).

R⁵ and R⁶ for Structural Formulas (II), (III) and (V) are eachindependently —H, —OH, a halogen, a lower alkoxy group or a lower alkylgroup.

For Structural Formula (VIII), R⁷ is —H or C1-C6 alkyl, preferably —H.

Values and preferred values of the remainder of the variables ofStructural Formulas (II)-(VIII) are each independently as describedabove in the first set of values for Structural Formula (I).

A third set of values for the variables in Structural Formulas(II)-(VIII) is provided in the following paragraphs:

R¹ is a phenyl group optionally substituted with one or moresubstituents selected from the group consisting of halogen, cyano,nitro, C1-C6 alkyl, C1-C6 haloalkyl, —OR³⁰, —SR³⁰, —N(R³¹)₂, Ar¹,—V_(o)—OR³⁰, —V_(o)—N(R³¹)₂, —V_(o)—Ar¹, —O—V_(o)—Ar¹, —O—V₁—N(R³¹)₂,—S—V_(o)—Ar¹, —S—V₁—N(R³¹)₂, —N(R³¹)—V_(o)—Ar¹, —N(R³¹)—V₁—N(R³¹)₂,—O—[CH₂]_(p)—O—, —S—[CH₂]_(p)—S—, or —[CH₂]_(q)—. Preferably, R¹ is aphenyl group optionally substituted with one or more substituentsselected from the group consisting of halogen, cyano, nitro, C1-C6alkyl, C1-C6 haloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, aryl,aryloxy, —OH, C1-C6 alkoxy, —O—[CH₂]_(p)—O— and —[CH₂]_(q)—.

Ar¹ is an aryl group each optionally substituted with one or moresubstituents selected from the group consisting of halogen, C1-C6 alkyl,amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano,hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl andC1-C6 haloalkyl. Preferably, Ar¹ is a phenyl group each optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy,C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl.

R³⁰ is independently hydrogen; an aryl group optionally substituted withone or more substituents selected from the group consisting of halogen,C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy,nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6alkylcarbonyl and C1-C6 haloalkyl; or an C1-C10 alkyl group optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino,C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl. Preferably, R³⁰is independently hydrogen; a phenyl group optionally substituted withone or more substituents selected from the group consisting of halogen,C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy,nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6alkylcarbonyl and C1-C6 haloalkyl; or a C1-C10 alkyl group optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino,C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl.

Each R³¹ is independently R³⁰, or —N(R³¹)₂ is an optionally substitutednon-aromatic heterocyclic group.

—N(R²R³) is a pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl ormorpholinyl group optionally substituted with one or more substituentsselected from the group consisting of halogen, C1-C5 alkyl, C1-C5haloalkyl, hydroxyl, C1-C5 alkoxy, nitro, cyano, C1-C5 alkoxycarbonyl,C1-C5 alkylcarbonyl or C1-C5 haloalkoxy, amino, C1-C5 alkylamino andC1-C5 dialkylamino.

R⁴ is an optionally substituted aryl or an optionally substituted lowerarylalkyl group. Example of suitable substituents are as described inthe first set of values for Structural Formula (I).

R⁵ and R⁶ for Structural Formulas (II), (III) and (V) are eachindependently —H, —OH, a halogen, a lower alkoxy group or a lower alkylgroup.

For Structural Formula (VIII), R⁷ is —H.

Preferably, Q in Structural Formula (II) is —O—, —S—, —C(O)—, —C(S)—,—NR⁷(CO)— or —C(O)NR⁷—

Values and preferred values of the remainder of the variables ofStructural Formulas (II)-(VIII) are each independently as describedabove in the first set of values for Structural Formula (I). Preferably,for Structural Formula (II), Q is —O—, —S—, —C(O)—, —C(S)—, —NR⁷(CO)— or—C(O)NR⁷—.

A fourth set of values for the variables in Structural Formulas(II)-(VIII) is provided in the following paragraphs:

R¹ is a phenyl group optionally substituted with one or moresubstituents selected from the group consisting of halogen, cyano,nitro, C1-C6 alkyl, C1-C6 haloalkyl, —OR³⁰, —SR³⁰, —N(R³¹)₂, Ar¹,—V_(o)—OR³⁰, —V_(o)—N(R³¹)₂, —V_(o)—Ar¹, —O—V_(o)—Ar¹, —O—V₁—N(R³¹)₂,—S—V_(o)—Ar¹, —S—V₁—N(R³¹)₂, —N(R³¹)—V_(o)—Ar¹, —N(R³¹)—V₁—N(R³¹)₂,—O—[CH₂]_(p)—O—, —S—[CH₂]_(p)—S—, or —[CH₂]_(q)—. Preferably, R¹ is aphenyl group optionally substituted with one or more substituentsselected from the group consisting of halogen, cyano, nitro, C1-C6alkyl, C1-C6 haloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, aryl,aryloxy, —OH, C1-C6 alkoxy, —O—[CH₂]_(p)—O— and —[CH₂]_(q)—.

Ar¹ is a phenyl group each optionally substituted with one or moresubstituents selected from the group consisting of halogen, C1-C6 alkyl,amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano,hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl andC1-C6 haloalkyl.

Each R³⁰ is independently hydrogen; a phenyl group optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy,C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; or aC1-C10 alkyl group optionally substituted with one or more substituentsselected from the group consisting of halogen, amino, C1-C6 alkylamino,C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6haloalkyl.

Each R³¹ is independently R³⁰, or —N(R³¹)₂ is an optionally substitutednon-aromatic heterocyclic group.

—N(R²R³) is a pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl ormorpholinyl group, which is optionally substituted with one or moresubstituents selected from the group consisting of halogen, C1-C5 alkyl,C1-C5 haloalkyl, hydroxyl, C1-C5 alkoxy, nitro, cyano, C1-C5alkoxycarbonyl, C1-C5 alkylcarbonyl or C1-C5 haloalkoxy, amino, C1-C5alkylamino and C1-C5 dialkylamino.

R⁴ is an optionally substituted aryl or an optionally substituted lowerarylalkyl group. Examples of suitable substitutents for R⁴ are asprovided above in the first set of values for Structural Formula (I).Preferably, R⁴ is selected from the group consisting of:

Each of rings A-Z5 is optionally and independently substituted.

For Structural Formula (VIII), R⁷ is —H.

Values and preferred values of the remainder of the variables ofStructural Formulas (II)-(VIII) are each independently as describedabove in the first set of values for Structural Formula (I). When thecompound of the invention is represented by Structural Formula (III) or(IV), or a pharmaceutically acceptable salt thereof, n is 1, 2, 3 or 4.Alternatively, when the compound of the invention is represented byStructural Formula (V) or (VI), or a pharmaceutically acceptable saltthereof, n is 3, 4 or 5.

A fifth set of values for the variables in Structural Formulas(II)-(VIII) independently is as defined in the first set, second set,third set, fourth set, fifth set, sixth set or seventh set of values forthe variables for Structural Formula (I).

In a third embodiment, the compound of the invention is represented byStructural Formula (IX) or (X):

or a pharmaceutically acceptable salt thereof. A first set of values forthe variables in Structural Formulas (IX) and (X) is defined in thefollowing paragraphs:

R¹ is a phenyl group optionally substituted with one or moresubstituents. Examples of suitable substituents include halogen, cyano,nitro, C1-C6 alkyl, C1-C6 haloalkyl, —OR³⁰, —SR³⁰, —N(R³¹)₂, Ar¹,—V_(o)—OR³⁰, —V_(o)—N(R³¹)₂, —V_(o)—Ar¹, —O—V_(o)—Ar¹, —O—V₁—N(R³¹)₂,—S—V_(o)—Ar¹, —S—V₁—N(R³¹)₂, —N(R³¹)—V_(o)—Ar¹, —N(R³¹)—V₁—N(R³¹)₂,—O—[CH₂]_(p)—O—, —S—[CH₂]_(p)—S—, and —[CH₂]_(q)—; preferably, R¹ is aphenyl group optionally substituted with one or more substituentsselected from the group consisting of —OH, —OCH₃, —OC₂H₅ and—O—[CH₂]_(p)—O—.

—N(R²R³) is a pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl ormorpholinyl group, which is optionally substituted with one or moresubstituents selected from the group consisting of halogen, C1-C5 alkyl,C1-C5 haloalkyl, hydroxyl, C1-C5 alkoxy, nitro, cyano, C1-C5alkoxycarbonyl, C1-C5 alkylcarbonyl or C1-C5 haloalkoxy, amino, C1-C5alkylamino and C1-C5 dialkylamino; preferably, —N(R²R³) is anunsubstituted pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl ormorpholinyl group.

Phenyl ring A is optionally substituted with one or more substituentsselected from the group consisting of halogen, cyano, nitro, C1-C10alkyl, C1-C10 haloalkyl, amino, C1-C10 alkylamino, C1-C10 dialkylamino,—OR⁵⁰, —Ar³, —V₄—Ar³, —V—OR⁵⁰, —O(C1-C10 haloalkyl), —V₄—O(C1-C10haloalkyl), —O—V₄—Ar³, —O—[CH₂]_(p′)—O— and —[CH₂]_(q′)—.

Ar³ is a phenyl group each optionally substituted with one or moresubstituents selected from the group consisting of halogen, C1-C6 alkyl,amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano,hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl andC1-C6 haloalkyl.

Each R⁵⁰ is independently hydrogen; a phenyl group optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy,C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; or anC1-C10 alkyl group optionally substituted with one or more substituentsselected from the group consisting of halogen, amino, C1-C6 alkylamino,C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6haloalkyl.

For Structural Formula (IX), n is 1, 2, 3 or 4. For Structural Formula(X), n is 3, 4 or 5.

Values and preferred values of the remainder of the variables ofStructural Formulas (IX) and (X) are each independently as defined abovein the first set of values for Structural Formula (I).

A second set of values and preferred values for the variables inStructural Formulas (IX) and (X) is as defined in the followingparagraphs:

R¹ is a phenyl group optionally substituted with one or moresubstituents selected from the group consisting of —OH, —OCH₃, —OC₂H₅and —O—[CH₂]_(p)—O—.

—N(R²R³) is pyrrolidinyl.

Phenyl ring A is optionally substituted with one or more substituentsselected from the group consisting of halogen, cyano, nitro, C1-C10alkyl, C1-C10 haloalkyl, amino, C1-C10 alkylamino, C1-C10 dialkylamino,aryl, aryloxy, hydroxy, C1-C10 alkoxy, —O—[CH₂]_(p′)—O— and—[CH₂]_(q′)—. Preferably, phenyl ring A is optionally substituted withone or more substituents selected from the group consisting of —OH,—OCH₃ or —OC₂H₅.

For Structural Formula (IX), n is 1, 2, 3 or 4. For Structural Formula(X), n is 3, 4 or 5.

Values and preferred values of the remaining variables of StructuralFormulas (IX) and (X) are each independently as described above in thefirst set of values for Structural Formula (I).

A third set of values for the variables in Structural Formulas (IX) and(X) independently is as defined in the first set, second set, third set,fourth set or fifth set, of values for Structural Formulas (II)-(VIII).

In a fourth embodiment, the compound of the invention is represented byStructural Formula (XI), (XII) or (XIII):

or a pharmaceutically acceptable salt thereof. A first set of values andpreferred values for the variables of Structural Formulas (XI)-(XIII) isdefined in the following paragraphs:

R¹ is a phenyl group optionally substituted with one or moresubstituents selected from the group consisting of halogen, cyano,nitro, C1-C6 alkyl, C1-C6 haloalkyl, —OR³⁰, —SR³⁰, —N(R³¹)₂, Ar¹,—V_(o)—OR³⁰, —V_(o)—N(R³¹)₂, —V_(o)—Ar¹, —O—V_(o)—Ar¹, —O—V₁—N(R³¹)₂,—S—V_(o)—Ar¹, —S—V₁—N(R³¹)₂, —N(R³¹)—V_(o)—Ar¹, —N(R³¹)—V₁—N(R³¹)₂,—O—[CH₂]_(p)—O—, —S—[CH₂]_(q)—S—, or —[CH₂]_(q)—. Preferably, R¹ is aphenyl group optionally substituted with one or more substituentsselected from the group consisting of halogen, cyano, nitro, C1-C6alkyl, C1-C6 haloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, aryl,aryloxy, —OH, C1-C6 alkoxy, —O—[CH₂]_(p)—O— and —[CH₂]_(q)—.

Ar¹ is an aryl group each optionally substituted with one or moresubstituents selected from the group consisting of halogen, C1-C6 alkyl,amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano,hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl andC1-C6 haloalkyl. Preferably, Ar¹ is a phenyl group each optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy,C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl.

R³⁰ is independently hydrogen; an aryl group optionally substituted withone or more substituents selected from the group consisting of halogen,C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy,nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6alkylcarbonyl and C1-C6 haloalkyl; or a C1-C10 alkyl group optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino,C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl. Preferably, R³⁰is independently hydrogen; a phenyl group optionally substituted withone or more substituents selected from the group consisting of halogen,C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy,nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6alkylcarbonyl and C1-C6 haloalkyl; or a C1-C10 alkyl group optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino,C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl.

Each R³¹ is independently R³⁰, or —N(R³¹)₂ is an optionally substitutednon-aromatic heterocyclic group. Examples of suitable substituents areas described above in the first set of values for Structural Formula(I).

R² and R³ taken together with the nitrogen atom of N(R²R³) form a 5- or6-membered, optionally-substituted non-aromatic heterocyclic ring.Examples of suitable substituents for the non-aromatic heterocyclicgroup represented by —NR²R³ are as described above in the first set ofvalues for Structural Formula (I).

R⁴ is an optionally substituted aryl group. Examples of suitablesubstituents for R⁴ are as provided above in the first set of values forStructural Formula (I).

R⁵ and R⁶ for Structural Formula (XI) are each independently —H, —OH, ahalogen, a lower alkoxy group or a lower alkyl group.

Values and preferred values of the remainder of the variables ofStructural Formulas (XI)-(XIII) are each independently as describedabove in the first set of values for Structural Formula (I).

A second set of values and preferred values for the variables ofStructural Formulas (XI)-(XIII) is defined in the following paragraphs:

R¹ is a phenyl group optionally substituted with one or moresubstituents selected from the group consisting of halogen, cyano,nitro, C1-C6 alkyl, C1-C6 haloalkyl, —OR³⁰, —SR³⁰, —N(R³¹)₂, Ar¹,—V_(o)—OR³⁰, —V_(o)—N(R³¹)₂, —V_(o)—Ar¹, —O—V_(o)—Ar¹, —O—V₁—N(R³¹)₂,—S—V_(o)—Ar¹, —S—V₁—N(R³¹)₂, —N(R³¹)—V_(o)—Ar¹, —N(R³¹)—V₁—N(R³¹)₂,—O—[CH₂]_(p)—O—, —S—[CH₂]_(p)—S—, or —[CH₂]_(q)—. Preferably, R¹ is aphenyl group optionally substituted with one or more substituentsselected from the group consisting of halogen, cyano, nitro, C1-C6alkyl, C1-C6 haloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, aryl,aryloxy, —OH, C1-C6 alkoxy, —O—[CH₂]_(p)—O—, and —[CH₂]_(q)—.

Ar¹ is a phenyl group each optionally substituted with one or moresubstituents selected from the group consisting of halogen, C1-C6 alkyl,amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano,hydroxy, C1-C6 haloalkoxy C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl andC1-C6 haloalkyl.

Each R³⁰ is independently hydrogen; a phenyl group optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy,C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; or anC1-C10 alkyl group optionally substituted with one or more substituentsselected from the group consisting of halogen, amino, C1-C6 alkylamino,C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6haloalkyl; and

Each R³¹ is independently R³⁰, or —N(R³¹)₂ is an optionally substitutednon-aromatic heterocyclic group.

—N(R²R³) is a pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl ormorpholinyl group, which is optionally substituted with one or moresubstituents selected from the group consisting of halogen, C1-C5 alkyl,C1-C5 haloalkyl, hydroxyl, C1-C5 alkoxy, nitro, cyano, C1-C5alkoxycarbonyl, C1-C5 alkylcarbonyl or C1-C5 haloalkoxy, amino, C1-C5alkylamino and C1-C5 dialkylamino.

R⁴ is an optionally substituted aryl group. Suitable substituents andpreferred substitutents are as provided above in the first set of valuesfor Structural Formula (I). Preferably, R⁴ is selected from the groupconsisting of:

Each of rings A-Z5 is optionally and independently substituted.Preferably, each of rings A-Z5 is optionally and independentlysubstituted with one or more substituents selected from Ar³ and Ar³—Ar³wherein values and preferred values of Ar³ are as described above forthe first set of values for Structural Formula (I). Preferably, Ar³ isan aryl group each optionally substituted with one or more substituentsselected from the group consisting of halogen, C1-C10 alkyl, C1-C10haloalkyl, hydroxy, C1-C10 alkoxy, nitro, cyano, C1-C10 alkoxycarbonyl,C1-C10 alkylcarbonyl, C1-C10 haloalkoxy, amino, C1-C10 alkylamino andC1-C10 dialkylamino. More preferably, Ar³ is an aryl group eachoptionally substituted with one or more substituents selected from thegroup consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy,C1-C4 alkoxy, nitro, cyano, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyl,C1-C4 haloalkoxy, amino, C1-C4 alkylamino and C1-C4 dialkylamino

R⁵ and R⁶ for Structural Formula (XI) are each independently —H, —OH, ahalogen, a lower alkoxy group or a lower alkyl group.

Values and preferred values of the remainder of the variables ofStructural Formulas (XI)-(XIII) are each independently as describedabove in the first set of values for Structural Formula (I).

A third set of values for the variables of Structural Formulas(XI)-(XIII) is defined in the following paragraphs:

R¹ is a phenyl group optionally substituted with one or moresubstituents selected from the group consisting of halogen, cyano,nitro, C1-C6 alkyl, C1-C6 haloalkyl, —OR³⁰, —SR³⁰, —N(R³¹)₂, Ar¹,—V_(o)—OR³⁰, —V_(o)—N(R³¹)₂, —V_(o)—Ar¹, —O—V_(o)—Ar¹, —O—V₁—N(R³¹)₂,—S—V_(o)—Ar¹, —S—V₁—N(R³¹)₂, —N(R³¹)—V_(o)—Ar¹, —N(R³¹)—V₁—N(R³¹)₂,—O—[CH₂]_(p)—O—, —S—[CH₂]_(p)—S—, or —[CH₂]_(q)—. Preferably, R¹ is aphenyl group optionally substituted with one or more substituentsselected from the group consisting of halogen, cyano, nitro, C1-C6alkyl, C1-C6 haloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, aryl,aryloxy, —OH, C1-C6 alkoxy, —O—[CH₂]_(p)—O—, and —[CH₂]_(q)—.

Ar¹ is a phenyl group each optionally substituted with one or moresubstituents selected from the group consisting of halogen, C1-C6 alkyl,amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano,hydroxy, C1-C6 haloalkoxy C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl andC1-C6 haloalkyl.

Each R³⁰ is independently hydrogen; a phenyl group optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy,C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; or aC1-C10 alkyl group optionally substituted with one or more substituentsselected from the group consisting of halogen, amino, C1-C6 alkylamino,C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6haloalkyl.

Each R³¹ is independently R³⁰, or —N(R³¹)₂ is an optionally substitutednon-aromatic heterocyclic group.

—N(R²R³) is an unsubstituted pyrrolidinyl, azetidinyl, piperidinyl,piperazinyl or morpholinyl group.

R⁴ is a biaryl group, such as a biphenyl group, optionally substitutedwith one or more substituents selected from the group consisting ofhalogen, cyano, amino, nitro, Ar³, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6alkoxy, hydroxy and C1-C6 haloalkoxy.

R⁵ and R⁶ for Structural Formula (XI) are each independently —H, —OH, ahalogen, a lower alkoxy group or a lower alkyl group, preferably —H.

Values and preferred values of the remainder of the variables ofStructural Formulas (XI)-(XIII) are each independently as describedabove in the first set of values for Structural Formula (I).

A fourth set of values for the variables of Structural Formulas(XI)-(XIII) is defined in the following paragraphs:

R¹ is a phenyl group optionally substituted with one or moresubstituents selected from the group consisting of —OH, —OCH₃, —OC₂H₅and —O—[CH₂]_(q)—O—, Preferably, R¹ is

where r is 1, 2, 3 or 4, preferably 1 or 2.

—N(R²R³) is an unsubstituted pyrrolidinyl group.

R⁴ is a biaryl group, such as a biphenyl group, optionally substitutedwith one or more substituents selected from the group consisting ofhalogen, cyano, amino, nitro, Ar³, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6alkoxy, hydroxy and C1-C6 haloalkoxy.

R⁵ and R⁶ for Structural Formula (XI) are each independently —H, —OH, ahalogen, a lower alkoxy group or a lower alkyl group, preferably —H.

n is an integer from 1 to 4.

Values and preferred values of the remainder of the variables ofStructural Formulas (XI)-(XIII) are each independently as describedabove in the first set of values for Structural Formula (I).

A fifth set of values preferred values for the variables of StructuralFormulas (XI)-(XIII) is defined in the following paragraphs:

R¹ is a phenyl group optionally substituted with one or moresubstituents selected from the group consisting of —OH, —OCH₃, —OC₂H₅and —O—[CH₂]_(p)—O—. Preferably R¹ is

where r is 1, 2, 3 or 4, preferably 1 or 2.

—N(R²R³) is pyrrolidinyl.

R⁴ is

optionally substituted with one or more substituents selected from thegroup consisting of halogen, cyano, amino, nitro, Ar³, C1-C6 alkyl,C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy and C1-C6 haloalkoxy.

n is 1.

R⁵ and R⁶ for Structural Formula (XI) are each independently —H, —OH, ahalogen, a lower alkoxy group or a lower alkyl group, preferably —H.

Values and preferred values of the remainder of the variables ofStructural Formulas (XI)-(XIII) are each independently as describedabove in the first set of values for Structural Formula (I).

A sixth set of values for the variables in Structural Formulas(XI)-(XIII) independently is as defined in the first set, second set,third set, fourth set, fifth set, sixth set or seventh set of values forStructural Formula (I).

In a fifth embodiment, the compound of the invention is represented byStructural Formula (XIV) or (XV):

or a pharmaceutically acceptable salt thereof. A first set of values andpreferred values for the variables in Structural Formulas (XIV) and (XV)is as defined in the following paragraphs:

R¹ is a phenyl group optionally substituted with one or moresubstituents selected from the group consisting of halogen, cyano,nitro, C1-C6 alkyl, C1-C6 haloalkyl, —OR³⁰, —SR³⁰, —N(R³¹)₂, Ar¹,—V_(o)—OR³⁰, —V_(o)—N(R³¹)₂, —V_(o)—Ar¹, —O—V_(o)—Ar¹, —O—V₁—N(R³¹)₂,—S—V_(o)—Ar¹, —S—V₁—N(R³¹)₂, —N(R³¹)—V_(o)—Ar¹, —N(R³¹)—V₁—N(R³¹)₂,—O—[CH₂]_(p)—O—, —S—[CH₂]_(p)—S—, or —[CH₂]_(q)—. Preferably, R¹ is aphenyl group optionally substituted with one or more substituentsselected from the group consisting of halogen, cyano, nitro, C1-C6alkyl, C1-C6 haloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, aryl,aryloxy, —OH, C1-C6 alkoxy, —O—[CH₂]_(p)—O—, and —[CH₂]_(q)—.

Ar¹ is a phenyl group each optionally substituted with one or moresubstituents selected from the group consisting of halogen, C1-C6 alkyl,amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano,hydroxy, C1-C6 haloalkoxy and C1-C6 haloalkyl.

Each R³⁰ is independently hydrogen; a phenyl group optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy,C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; or aC1-C10 alkyl group optionally substituted with one or more substituentsselected from the group consisting of halogen, amino, C1-C6 alkylamino,C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6haloalkyl.

Each R³¹ is independently R³⁰, or —N(R³¹)₂ is an optionally substitutednon-aromatic heterocyclic group.

—N(R²R³) is a pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl ormorpholinyl group optionally substituted with one or more substituentsselected from the group consisting of halogen, C1-C5 alkyl, C1-C5haloalkyl, hydroxyl, C1-C5 alkoxy, nitro, cyano, C1-C5 alkoxycarbonyl,C1-C5 alkylcarbonyl or C1-C5 haloalkoxy, amino, C1-C5 alkylamino andC1-C5 dialkylamino.

k is 0, 1, 2, 3, 4, 5 or 6.

R⁸ is —H, or an optionally substituted aryl or an optionally substitutedlower alkyl group. Examples of suitable substituents are as describedfor the first set of values for Structural Formula (I). Preferably, R⁸is selected from the group consisting of:

Each of rings A-Z5 is optionally and independently substituted. Examplesof suitable substituents for R⁸ are as provided above in the first setof values for R⁴ in Structural Formula (I). More preferably, R⁸ is a

group. Alternatively, R⁸ is an aryl group substituted with Ar³, such asa phenyl group substituted with Ar³, where values and preferred valuesof Ar³ are as described above in Structural Formula (I).

Values and preferred values of the remainder of the variables ofStructural Formulas (XIV) and (XV) are each independently as describedabove in the first set of values for Structural Formula (I).

A second set of values for the variables in Structural Formulas (XIV)and (XV) is defined in the following paragraphs:

R¹ is a phenyl group optionally substituted with one or moresubstituents selected from the group consisting of halogen, cyano,nitro, C1-C6 alkyl, C1-C6 haloalkyl, —OR³⁰, —SR³⁰, —N(R³¹)₂, Ar¹,—V—OR³⁰, —V—N(R³¹)₂, —V—Ar¹, —O—V—Ar¹, —O—V₁—N(R³¹)₂, —S—V—Ar¹,—S—V₁—N(R³¹)₂, —N(R³¹)—V—Ar¹, —N(R³¹)—V₁—N(R³¹)₂, —O—[CH₂]_(p)—O—,—S—[CH₂]_(p)—S— and —[CH₂]_(q)—.

Ar¹ is a phenyl group each optionally substituted with one or moresubstituents selected from the group consisting of halogen, C1-C6 alkyl,amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano,hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl andC1-C6 haloalkyl.

Each R³⁰ is independently hydrogen; a phenyl group optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy,C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; or anC1-C10 alkyl group optionally substituted with one or more substituentsselected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy,C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6haloalkyl.

Each R³¹ is independently R³⁰, or —N(R³¹)₂ is an optionally substitutednon-aromatic heterocyclic group.

—N(R²R³) is an unsubstituted pyrrolidinyl, azetidinyl, piperidinyl,piperazinyl or morpholinyl group, preferably an unsubstitutedpyrrolidinyl group.

Values and preferred values for k and R⁸ are as provided above in thefirst set of values for Structural Formulas (XIV) and (XV).

Values and preferred values of the remainder of the variables ofStructural Formulas (XIV) and (XV) are each independently as describedabove in the first set of values for Structural Formula (I).

A third set of values for the variables in Structural Formulas (XIV) and(XV) is defined in the following paragraphs:

R¹ is a phenyl group optionally substituted with one or moresubstituents selected from the group consisting of —OH, —OCH₃, —OC₂H₅and —O—[CH₂]_(p)—O—. Preferably R¹ is

where r is 1, 2, 3 or 4, preferably 1 or 2.

—N(R²R³) is pyrrolidinyl.

Values and preferred values for k and R⁸ are each independently asprovided above in the first set of values for Structural Formulas (XIV)and (XV).

Values and preferred values of the remainder of the variables ofStructural Formulas (XIV) and (XV) are each independently as describedabove in the first set of values for Structural Formula (I).

A fourth set of values for the variables in Structural Formulas(XIV)-(XV) is as defined in the first set, second set, third set, fourthset, fifth set, sixth set or seventh set for Structural Formula (I).

In a sixth embodiment, the compound of the invention is represented byStructural Formula (XXI):

or a pharmaceutically acceptable salt thereof. A first set of values andpreferred values for the variables in Structural Formula (XXI) is asdefined in the following paragraphs:

Each of A and B independently is halogen, hydroxy, C1-C6 alkyl, C1-C6haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy.

k′ is 0, 1 or 2.

k″ is 0, 1 or 2. Preferably, k″ is 0 or 1. More preferably k″ is 1.

m′ is 0, 1 or 2. Preferably, m′ is 1.

Values and preferred values for the remainder of the variables ofStructural Formula (XXI) are each independently as described above inthe first set of values for Structural Formula (I).

A second set of values for the variables in Structural Formula (XXI) isprovided in the following paragraphs:

Y is —H, —C(O)R, —C(O)OR or —C(O)NRR′, preferably —H.

Values and preferred values for A, B, k′, k″ and m′ are eachindependently as described above in the first set of values forStructural Formula (XXI).

Values and preferred values for the remainder of the variables ofStructural Formula (XXI) are each independently as described above inthe first set of values for Structural Formula (I).

A third set of values for the variables in Structural Formula (XXI) isprovided in the following paragraphs:

R³⁰ is independently hydrogen; an aryl group optionally substituted withone or more substituents selected from the group consisting of halogen,C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy,nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6alkylcarbonyl and C1-C6 haloalkyl; or a C1-C10 alkyl group optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino,C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl. Preferably, R³⁰is independently hydrogen; a phenyl group optionally substituted withone or more substituents selected from the group consisting of halogen,C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy,nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6alkylcarbonyl and C1-C6 haloalkyl; or a C1-C10 alkyl group optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino,C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl. Morepreferably, R³⁰ is independently hydrogen; or a C1-C10 alkyl groupoptionally substituted with one or more substituents selected from thegroup consisting of halogen, amino, C1-C6 alkylamino, C1-C6dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy,C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl. Even morepreferably, R³⁰ is independently hydrogen, or a C1-C10 alkyl groupoptionally substituted with one or more substituents selected from thegroup consisting of halogen, C1-C6 alkoxy, C1-C6 haloalkoxy and hydroxy.

Values and preferred values for A, B, Y, k′, k″ and m′ are eachindependently as described above in the second set of values forStructural Formula (XXI).

Values and preferred values for the remainder of the variables ofStructural Formula (XXI) are each independently as described above inthe first set of values for Structural Formula (I).

A fourth set of values for the variables in Structural Formula (XXI) isprovided in the following paragraphs:

Y is —H.

Values and preferred values for R³⁰, A, B, k′, k″ and m′ are eachindependently as described above in the third set of values forStructural Formula (XXI).

Values and preferred values for the remainder of the variables ofStructural Formula (XXI) are each independently as described above inthe first set of values for Structural Formula (I).

In a seventh embodiment, the compound of the invention is represented byStructural Formula (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII),(XXVIII), (XXIX), (XXX) or (XXXI):

or a pharmaceutically acceptable salt thereof. A first set of values andpreferred values for the variables in Structural Formulas (XXII)-(XXXI)is as defined in the following paragraphs:

Each of A and B independently is halogen, hydroxy, C1-C6 alkyl, C1-C6haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy.

Each R³⁰ is independently hydrogen; a phenyl group optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy,C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; or aC1-C10 alkyl group optionally substituted with one or more substituentsselected from the group consisting of halogen, amino, C1-C6 alkylamino,C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6haloalkyl. Preferably, R³⁰ is independently hydrogen; or a C1-C10 alkylgroup optionally substituted with one or more substituents selected fromthe group consisting of halogen, amino, C1-C6 alkylamino, C1-C6dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy,C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl. Morepreferably, R³⁰ is independently hydrogen, or a C1-C10 alkyl groupoptionally substituted with one or more substituents selected from thegroup consisting of halogen, C1-C6 alkoxy, C1-C6 haloalkoxy and hydroxy.

Each k′ is independently 0, 1 or 2.

Each k″ is independently 0, 1 or 2.

Each m′ is independently 0, 1 or 2. Preferably, each m′ is 1.

Each n is independently 1, 2, 3, 4, 5 or 6. Preferably, each n inStructural Formulas (XXV) and (XXVI) is independently 1, 2, 3 or 4, andeach n in Structural Formulas (XXIII) or (XXIV) is independently 2, 3, 4or 5.

Values and preferred values for the remainder of the variables ofStructural Formulas (XXII)-(XXXI) are each independently as describedabove in the first set of values for Structural Formula (I).

A second set of values for the variables in Structural Formulas(XXII)-(XXXI) is provided in the following paragraphs:

Each R⁴ in Structural Formulas (XXII)-(XXVIII) is independently analiphatic or aryl group each optionally substituted with one or moresubstituents described above in the first set of values for StructuralFormula (I). Preferably, each R⁴ in Structural Formulas (XXII)-(XXVIII)is independently an optionally substituted aryl or an optionallysubstituted lower arylalkyl group. Examples of suitable substituents areas described in the first set of values for Structural Formula (I).

Each R⁴ in Structural Formulas (XXIX)-(XXXI) is independently an arylgroup optionally substituted with one or more substituents describedabove in the first set of values for Structural Formula (I).

R⁵ and R⁶ in Structural Formulas (XXII), (XXIII), (XV) and (XXIX) areeach independently —H, —OH, a halogen, a C1-C6 alkoxy group or a C1-C6alkyl group.

For Structural Formula (XXVIII), R⁷ is —H or C1-C6 alkyl, preferably —H.

Values and preferred values for A, B, R³⁰, k′, k″, m′ and n are eachindependently as described above in the first set of values for thevariables in Structural Formulas (XXII)-(XXXI). Preferably, each n inStructural Formulas (XXV) and (XXVI) is independently 1, 2, 3 or 4, andeach n in Structural Formulas (XXIII) or (XXIV) is independently 2, 3, 4or 5.

Values and preferred values for the remainder of the variables ofStructural Formulas (XXII)-(XXXI) are each independently as describedabove in the first set of values for Structural Formula (I).

A third set of values for the variables in Structural Formulas(XXII)-(XXXI) is provided in the following paragraphs:

Each R⁴ in Structural Formulas (XXII)-(XXVIII) is independently anoptionally substituted aryl or an optionally substituted lower arylalkylgroup. Example of suitable substituents are as described in the firstset of values for Structural Formula (I). Each R⁴ in Structural Formulas(XXIX)-(XXXI) is independently an aryl group optionally substituted withone or more substituents described above in the first set of values forStructural Formula (I).

R⁵ and R⁶ for Structural Formulas (XXII), (XXIII), (XXV) and (XXIX) areeach independently —H, —OH, a halogen, a lower alkoxy group or a loweralkyl group.

For Structural Formula (XXVIII), R⁷ is —H.

Q in Structural Formula (XXII) is —O—, —S—, —C(O)—, —C(S)—, —NR⁷(CO)— or—C(O)NR⁷—.

Values and preferred values for A, B, R³⁰, k′, k″, m′ and n are eachindependently as described above in the first set of values for thevariables in Structural Formulas (XXII)-(XXXI). Preferably, each n inStructural Formulas (XXV) and (XXVI) is independently 1, 2, 3 or 4, andeach n in Structural Formulas (XXIII) or (XXIV) is independently 2, 3, 4or 5.

Values and preferred values for the remainder of the variables ofStructural Formulas (XXII)-(XXXI) are each independently as describedabove in the first set of values for Structural Formula (I).

A fourth set of values for the variables in Structural Formulas(XXII)-(XXXI) is provided in the following paragraphs:

Each R⁴ in Structural Formulas (XXII)-(XXVIII) is independently selectedfrom the group consisting of:

wherein each x is independently 0 or 1, and each of rings A-Z5 isoptionally and independently substituted.

Each R⁴ in Structural Formulas (XXIX)-(XXXI) is independently selectedfrom the group consisting of:

wherein each of rings A-Z5 is optionally and independently substituted.Preferably, each R⁴ in Structural Formulas (XXII)-(XXXI) isindependently monocyclic.

Example of suitable substituents for rings A-Z5 are as described in thefirst set of values for Structural Formula (I).

Preferably, in Structural Formulas (XXIX)-(XXXI), each of rings A-Z5 isoptionally and independently substituted with one or more substituentsselected from Ar³ and Ar³—Ar³ wherein values and preferred values of Ar³are as described above for the first set of values for StructuralFormula (I). Preferably, Ar³ is an aryl group each optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, C1-C10 alkyl, C1-C10 haloalkyl, hydroxy, C1-C10alkoxy, nitro, cyano, C1-C10 alkoxycarbonyl, C1-C10 alkylcarbonyl,C1-C10 haloalkoxy, amino, C1-C10 alkylamino and C1-C10 dialkylamino.More preferably, Ar³ is an aryl group each optionally substituted withone or more substituents selected from the group consisting of halogen,C1-C4 alkyl, C1-C4 haloalkyl, hydroxy, C1-C4 alkoxy, nitro, cyano, C1-C4alkoxycarbonyl, C1-C4 alkylcarbonyl, C1-C4 haloalkoxy, amino, C1-C4alkylamino and C1-C4 dialkylamino.

Values and preferred values for R⁵, R⁶, R⁷, R³⁰, Q, k′, k″, m′ and n areeach independently as described above in the third set of values for thevariables in Structural Formulas (XXII)-(XXXII). Preferably, each n inStructural Formulas (XXV) and (XXVI) is independently 1, 2, 3 or 4, andeach n in Structural Formulas (XXIII) or (XXIV) is independently 2, 3, 4or 5.

Values and preferred values for the remainder of the variables ofStructural Formulas (XXII)-(XXXI) are each independently as describedabove in the first set of values for Structural Formula (I).

A fifth set of values for the variables in Structural Formulas(XXII)-(XXXI) is provided in the following paragraphs:

Each R⁴ in Structural Formulas (XXII)-(XXVIII) is independently

wherein x is 0 or 1.

Each R⁴ in Structural Formulas (XXIX)-(XXXI) is independently

Each ring A is optionally substituted. Example of suitable substituentsfor rings A are as described in the first set of values for StructuralFormula (I). Preferably, ring A is optionally substituted with one ormore substituents selected from the group consisting of halogen, cyano,amino, nitro, Ar³, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxyand C1-C6 haloalkoxy.

Ar³ is an aryl group each optionally substituted with one or moresubstituents selected from the group consisting of halogen, C1-C4 alkyl,C1-C4 haloalkyl, hydroxy, C1-C4 alkoxy, nitro, cyano, C1-C4alkoxycarbonyl, C1-C4 alkyl carbonyl, C1-C4 haloalkoxy, amino, C1-C4alkylamino and C1-C4 dialkylamino

Values and preferred values for A, B, R⁵, R⁶, R⁷, R³⁰, Q, k′, k″, m′ andn are each independently as described above in the fourth set of valuesfor the variables in Structural Formulas (XXII)-(XXXI).

Values and preferred values for the remainder of the variables ofStructural Formulas (XXII)-(XXXI) are each independently as describedabove in the first set of values for Structural Formula (I).

A sixth set of values for the variables other than A, B, k′, k″ and m′in Structural Formulas (XXII)-(XXXI) is as defined in the first set,second set, third set, fourth set, fifth set, sixth set or seventh setof values for the variables for Structural Formula (I), and values andpreferred values for A, B, k′, k″ and m′ are each independently asdescribed above in the first set of values for the variables inStructural Formulas (XXII)-(XXXI).

In an eighth embodiment, the compound of the invention is represented byStructural Formula (XXXII) or (XXXIII):

or a pharmaceutically acceptable salt thereof. A first set of values andpreferred values for the variables in Structural Formulas(XXXII)-(XXXIII) is as defined in the following paragraphs:

Each of A and B independently is halogen, hydroxy, C1-C6 alkyl, C1-C6haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy.

Each R³⁰ is independently hydrogen; a phenyl group optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy,C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; or aC1-C10 alkyl group optionally substituted with one or more substituentsselected from the group consisting of halogen, amino, C1-C6 alkylamino,C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6haloalkyl. Preferably, R³⁰ is independently hydrogen; or a C1-C10 alkylgroup optionally substituted with one or more substituents selected fromthe group consisting of halogen, amino, C1-C6 alkylamino, C1-C6dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy,C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl. Morepreferably, R³⁰ is independently hydrogen, or a C1-C10 alkyl groupoptionally substituted with one or more substituents selected from thegroup consisting of halogen, C1-C6 alkoxy, C1-C6 haloalkoxy and hydroxy.

Each k′ is independently 0, 1 or 2.

Each k″ is independently 0, 1 or 2.

Each m′ is independently 0, 1 or 2.

Each q is independently 0, 1, 2, 3, 4, 5 or 6.

Each R⁸ independently is —H, or an optionally substituted aryl or anoptionally substituted lower alkyl group. Examples of suitablesubstituents are as described for the first set of values for StructuralFormula (I). Preferably, each R⁸ independently is selected from thegroup consisting of:

Each of rings A-Z5 is optionally and independently substituted. Examplesof suitable substituents for R⁸ are as provided above in the first setof values for R⁴ in Structural Formula (I). More preferably, each R⁸ isindependently a

group. Alternatively, each R⁸ is independently an aryl group substitutedwith Ar³, such as a phenyl group substituted with Ar³, where values andpreferred values of Ar³ are as described above in Structural Formula(I).

Values and preferred values for the remainder of the variables ofStructural Formulas (XXXII)-(XXXIII) are each independently as describedabove in the first set of values for Structural Formula (I).

In one preferred embodiment, each k′ in Structural Formulas(XXI)-(XXXIII) is independently 0 or 1. Preferably, when k′ is 1, each Aindependently is positioned at a meta position of the phenyl ring.

In another preferred embodiment, each k″ in Structural Formulas(XXI)-(XXXIII) is independently 0 or 1, more preferably 1.

In yet another preferred embodiment, each m′ in Structural Formulas(XXI)-(XXXIII) is independently 1.

In yet another preferred embodiment, each k′ in Structural Formulas(XXI)-(XXXIII) is independently 0 or 1; and each k″ in StructuralFormulas (XXI)-(XXXIII) is independently 0 or 1, more preferably 1.

In yet another preferred embodiment, in Structural Formulas(XXI)-(XXXIII):

Each R³⁰ is independently hydrogen or a C1-C6 alkyl group optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, amino, C1-C3 alkylamino, C1-C3 dialkylamino,C1-C3 alkoxy, nitro, cyano, hydroxy, C1-C3 haloalkoxy, C1-C3alkoxycarbonyl and C1-C3 alkylcarbonyl;

each k′ in Structural Formulas (XXI)-(XXXIV) is independently 0 or 1.Preferably, when k′ is 1, each A independently is positioned at a metaposition of the phenyl ring; and

each k″ in Structural Formulas (XXI)-(XXXIV) is independently 0 or 1,preferably 1.

In yet another preferred embodiment, in Structural Formulas(XXI)-(XXXIII):

Each —OR³⁰ is independently —OH or —O—C1-C6 alkyl optionally substitutedwith one or more substituents selected from the group consisting ofhalogen, C1-C3 C1-C3 alkoxy, hydroxy and C1-C3 haloalkoxy;

each k′ in Structural Formulas (XXI)-(XXXIII) is independently 0 or 1.Preferably, when k′ is 1, each A is independently positioned at a metaposition of the phenyl ring; and

each k″ in Structural Formulas (XXI)-(XXXIII) is independently 0 or 1,preferably 1.

In one more preferred embodiment, the compound of the invention isrepresented by Structural Formula (XVIA) or (XVIB):

or a pharmaceutically acceptable salt thereof, wherein: Q is —O—, —C(O)—or —NH, specifically, —O— or —C(O)—; r and s are each independently 1,2, 3 or 4; each n independently is 1, 2, 3, 4, 5 or 6; and R⁴ has valuesand preferred values provided above in the first set of values forStructural Formula (I).

In another more preferred embodiment, the compound of the invention isrepresented by Structural Formula (XVIC) or (XVID):

or a pharmaceutically acceptable salt thereof, wherein:

Q is —O—, —C(O)— or —NH, specifically, —O— or —C(O)—;

r and s are each independently 1, 2, 3 or 4;

each n independently is 1, 2, 3, 4, 5 or 6;

R⁴ has values and preferred values provided above in the first set ofvalues for Structural Formula (I); and

B is halogen, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy orC1-C6 haloalkoxy. Preferably, B is halogen, hydroxy, C1-C5 alkoxy orC1-C5 haloalkoxy.

In another more preferred embodiment, the compound of the invention isrepresented by Structural Formula (XVII), (XVIII), (XIX) or (XIX):

or a pharmaceutically acceptable salt thereof, wherein phenyl ring A isoptionally substituted; each n is 1, 2, 3, 4, 5, or 6; and k is 0, 1 or2. Values and preferred values of suitable substituents of phenyl ring Aare as described above in the first set of values for Structural Formula(I).

In all of the embodiments described above for Structural Formulas(XXI)-(XXXIII) and (XVIC)-(XVID), the heterocyclic ring represented by

can be replaced with a bridged heterobicyclic ring comprising 5-12 ringcarbon atoms and 1 or 2 nitrogen atoms. The invention also includescompounds represented by Structural Formulas (XXI)-(XXXIII) and(XVIC)-(XVID) with this replacement of

with a bridged heterobicyclic ring comprising 5-12 ring carbon atoms and1 or 2 nitrogen atoms. Values, including preferred values, for thevariables other than B, k″ and m′ in Structural Formulas (XXI)-(XXXIII)and (XVIC)-(XVID) are as defined above with respect to StructuralFormulas (XXI)-(XXXIIII) and (XVIC)-(XVID).

Similarly, in all of the embodiments described above for StructuralFormulas (I)-(XX), the non-aromatic heterocyclic ring represented by—NR²R³ can be a bridged heterobicyclic ring comprising 5-12 ring carbonatoms and 1 or 2 nitrogen atoms.

Examples of bridged heterobicyclic ring comprising 5-12 ring carbonatoms and 1 or 2 nitrogen atoms include

The bridged bicyclic ring carbon atoms can be optionally substitutedwith one or more substituents selected from the group consisting ofhalogen, cyano, nitro, —OH, —SH, —O(C1-C6 alkyl), —S(C1-C6 alkyl),—O(C1-C6 haloalkyl), —S(C1-C6 haloalkyl), C1-C6 alkyl, C1-C6 haloalkyl,amino, C1-C6 alkylamino and C1-C6 dialkylamino. Alternatively, thebridged bicyclic ring carbon atoms can be optionally substituted withone or more substituents selected from the group consisting of halogen,—OH, —O(C1-C6 alkyl) and —O(C1-C6 haloalkyl). The bridged bicyclic ringnitrogen atoms can be optionally substituted with one or moresubstituents selected from the group consisting of C1-C6 alkyl andphenyl, the alkyl being optionally substituted with halogen, cyano,nitro, —OH, —SH, —O(C1-C6 alkyl), —S(C1-C6 alkyl), —O(C1-C6 haloalkyl),—S(C1-C6 haloalkyl), phenyl, amino, C1-C6 alkylamino and C1-C6dialkylamino, and the phenyl being optionally substituted with halogen,cyano, nitro, —OH, —SH, —O(C1-C6 alkyl), —S(C1-C6 alkyl), —O(C1-C6haloalkyl), —S(C1-C6 haloalkyl), C1-C6 alkyl, C1-C6 haloalkyl, amino,C1-C6 alkylamino and C1-C6 dialkylamino. Alternatively, the bridgedbicyclic ring nitrogen atoms can be optionally substituted with C1-C6alkyl that is optionally substituted with halogen, —OH, —O(C1-C6 alkyl)and —O(C1-C6 haloalkyl).

In another embodiment, the compound of the invention is represented by astructural formula selected from Structural Formulas (I)-(VIII) and(XI)-(XV), wherein values, including preferred values, of the variablesin the structural formulas, other than R³⁰, R³¹ and R³² for thesubstituents of R¹, are independently as defined in each embodimentdescribed above for Structural Formulas (I)-(VIII) and (XI)-(XV). Inthis embodiment, each R³⁰ is independently: i) hydrogen; ii) an arylgroup optionally substituted with one or more substituents selected fromthe group consisting of halogen, alkyl, amino, alkylamino, dialkylamino,alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyland haloalkyl; or iii) an alkyl group optionally substituted with one ormore substituents selected from the group consisting of halogen, amino,nitro, cyano, hydroxy, phenyl, phenylamino, diphenylamino, aryloxy,benzoyl, phenoxycarbonyl, alkylamino, dialkylamino, alkoxy,alkoxycarbonyl and alkylcarbonyl. Each R³¹ is independently R³⁰,—CO₂R³⁰, —SO₂R³⁰ or —C(O)R³⁰; or —N(R³¹)₂ taken together is anoptionally substituted non-aromatic heterocyclic group. Each R³² isindependently: i) an aryl group optionally substituted with one or moresubstituents selected from the group consisting of halogen, alkyl,amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy,haloalkoxy, alkylcarbonyl and haloalkoxy and haloalkyl; or ii) an alkylgroup optionally substituted with one or more substituents selected fromthe group consisting of halogen, amino, nitro, cyano, hydroxy, phenyl,phenylamino, diphenylamino, aryloxy, benzoyl, phenoxycarbonyl,alkylamino, dialkylamino, alkoxy, alkoxycarbonyl and alkylcarbonyl. Eachof the phenyl, phenylamino, diphenylamino, aryloxy, benzoyl,phenoxycarbonyl for the substituents of the alkyl group represented byR³⁰ and R³² is independently and optionally substituted with one or moresubstituents selected from the group consisting of halogen, hydroxy,cyano, nitro, amino, C1-C5 alkyl, C1-C5 haloalkyl, C1-C5 alkoxy, C1-C5haloalkoxy, C1-C5 alkylamino, C1-C5 dialkylamino, (C1-C5 alkoxy)carbonyland (C1-C5 alkyl)carbonyl. Each of the alkylamino, dialkylamino, alkoxy,alkoxycarbonyl and alkylcarbonyl for the substituents of the alkyl grouprepresented by R³⁰ and R³² is independently and optionally substitutedwith one or more substituents selected from the group consisting ofhalogen, hydroxy, cyano, nitro, amino, phenyl, C1-C5 alkoxy, C1-C5haloalkoxy, phenylamino, C1-C5 alkylamino, C1-C5 dialkylamino,diphenylamino, (C1-C5 alkoxy)carbonyl, (C1-C5 alkyl)carbonyl, benzoyland phenoxycarbonyl.

Specific examples of the compounds of the invention are shown below:

and pharmaceutically acceptable salts thereof.

Other specific examples of the compounds of the invention includecompounds shown in Tables 1 and 2 and those exemplified in the examplesbelow, stereoisomers thereof, and pharmaceutically acceptable saltsthereof.

Also included are solvates, hydrates or polymorphs of the disclosedcompounds herein. Thus, it is to be understood that when any compound isreferred to herein by name and structure, solvates, hydrates andpolymorphs thereof are included.

The compounds of the invention may contain one or more chiral centersand/or double bonds and, therefore, may exist as stereoisomers, such asdouble-bond isomers (i.e., geometric isomers), enantiomers, ordiastereomers. When compounds of the invention are depicted or namedwithout indicating the stereochemistry, it is to be understood that bothstereomerically pure forms (e.g., geometrically pure, enantiomericallypure, or diastereomerically pure) and stereoisomeric mixtures areencompassed. For example, the compound represented by Structural Formula(I) below has chiral centers 1 and 2. Accordingly, the compounds of theinvention depicted by Structural Formula (I) include (1R,2R), (1R,2S),(1S,2R) and (1S,2S) stereoisomers and mixtures thereof.

As used herein, a racemic mixture means about 50% of one enantiomer andabout 50% of is corresponding enantiomer relative to all chiral centersin the molecule. The invention encompasses all enantiomerically-pure,enantiomerically-enriched, diastereomerically pure, diastereomericallyenriched, and racemic mixtures of the compounds of the invention.

In some preferred embodiments, the compounds of the invention are(1R,2R) stereoisomers.

Enantiomeric and diastereomeric mixtures can be resolved into theircomponent enantiomers or stereoisomers by well known methods, such aschiral-phase gas chromatography, chiral-phase high performance liquidchromatography, crystallizing the compound as a chiral salt complex, orcrystallizing the compound in a chiral solvent. Enantiomers anddiastereomers can also be obtained from diastereomerically- orenantiomerically-pure intermediates, reagents, and catalysts by wellknown asymmetric synthetic methods.

Included in the invention are pharmaceutically acceptable salts of thecompounds disclosed herein. The disclosed compounds have basic aminegroups and therefore can form pharmaceutically acceptable salts withpharmaceutically acceptable acid(s). Suitable pharmaceuticallyacceptable acid addition salts of the compounds of the invention includesalts of inorganic acids (such as hydrochloric acid, hydrobromic,phosphoric, metaphosphoric, nitric, and sulfuric acids) and of organicacids (such as, acetic acid, benzenesulfonic, benzoic, citric,ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic,lactobionic, maleic, malic, methanesulfonic, succinic,p-toluenesulfonic, and tartaric acids). Compounds of the invention withacidic groups such as carboxylic acids can form pharmaceuticallyacceptable salts with pharmaceutically acceptable base(s). Suitablepharmaceutically acceptable basic salts include ammonium salts, alkalimetal salts (such as sodium and potassium salts) and alkaline earthmetal salts (such as magnesium and calcium salts). Compounds with aquaternary ammonium group also contain a counteranion such as chloride,bromide, iodide, acetate, perchlorate and the like. Other examples ofsuch salts include hydrochlorides, hydrobromides, sulfates,methanesulfonates, nitrates, maleates, acetates, citrates, fumarates,tartrates [e.g. (+)-tartrates, (−)-tartrates or mixtures thereofincluding racemic mixtures], succinates, benzoates and salts with aminoacids such as glutamic acid.

When the stereochemistry of the disclosed compounds is named or depictedby structure, the named or depicted stereoisomer is at least 60%, 70%,80%, 90%, 99% or 99.9% by weight pure relative to the otherstereoisomers. When a single enantiomer is named or depicted bystructure, the depicted or named enantiomer is at least 60%, 70%, 80%,90%, 99% or 99.9% by weight optically pure. Percent optical purity byweight is the ratio of the weight of the enantiomer over the weight ofthe enantiomer plus the weight of its optical isomer.

As used herein, the term “hydrolyzable group” means an amide, ester,carbamate, carbonate, ureide, or phosphate analogue, respectively, thateither: 1) does not destroy the biological activity of the compound andconfers upon that compound advantageous properties in vivo, such asimproved water solubility, improved circulating half-life in the blood(e.g., because of reduced metabolism of the prodrug), improved uptake,improved duration of action, or improved onset of action; or 2) isitself biologically inactive but is converted to a biologically activecompound. Examples of hydrolyzable amides include, but are not limitedto, lower alkyl amides, α-amino acid amides, alkoxyacyl amides, andalkylaminoalkylcarbonyl amides. Examples of biohydrolyzable estersinclude, but are not limited to, lower alkyl esters, alkoxyacyloxyesters, alkyl acylamino alkyl esters, and choline esters. Examples ofbiohydrolyzable carbamates include, but are not limited to, loweralkylamines, substituted ethylenediamines, aminoacids,hydroxyalkylamines, heterocyclic and heteroaromatic amines, andpolyether amines.

An “aliphatic group” is non-aromatic, consists solely of carbon andhydrogen and may optionally contain one or more units of unsaturation,e.g., double and/or triple bonds. An aliphatic group may be straightchained, branched or cyclic. When straight chained or branched, analiphatic group typically contains between about one and about twentycarbon atoms, typically between about one and about ten carbon atoms,more typically between about one and about six carbon atoms. Whencyclic, an aliphatic group typically contains between about three andabout ten carbon atoms, more typically between about three and aboutseven carbon atoms. A “substituted aliphatic group” is substituted atany one or more “substitutable carbon atom”. A “substitutable carbonatom” in an aliphatic group is a carbon in an aliphatic group that isbonded to one or more hydrogen atoms. One or more hydrogen atoms can beoptionally replaced with a suitable substituent group. A “haloaliphaticgroup” is an aliphatic group, as defined above, substituted with one ormore halogen atoms. Suitable substituents on a substitutable carbon atomof an aliphatic group are the same as those for an alkyl group.

The term “alkyl” used alone or as part of a larger moiety, such as“alkoxy”, “haloalkyl”, “arylalkyl”, “alkylamine”, “cycloalkyl”,“dialkyamine”, “alkylamino”, “dialkyamino” “alkylcarbonyl”,“alkoxycarbonyl” and the like, includes as used herein means saturatedstraight-chain, cyclic or branched aliphatic group. As used herein, aC1-C6 alkyl group is referred to “lower alkyl.” Similarly, the terms“lower alkoxy”, “lower haloalkyl”, “lower arylalkyl”, “loweralkylamine”, “lower cycloalkylalkyl”, “lower dialkyamine”, “loweralkylamino”, “lower dialkyamino” “lower alkylcarbonyl”, “loweralkoxycarbonyl” include straight and branched saturated chainscontaining one to six carbon atoms.

The term “alkoxy” means —O-alkyl; “hydroxyalkyl” means alkyl substitutedwith hydroxy; “aralkyl” means alkyl substituted with an aryl group;“alkoxyalkyl” mean alkyl substituted with an alkoxy group; “alkylamine”means amine substituted with an alkyl group; “cycloalkylalkyl” meansalkyl substituted with cycloalkyl; “dialkylamine” means aminesubstituted with two alkyl groups; “alkylcarbonyl” means —C(O)—R*,wherein R* is alkyl; “alkoxycarbonyl” means —C(O)—OR*, wherein R* isalkyl; and where alkyl is as defined above.

The terms “amine” and “amino” are used interchangeably throughout hereinand mean —NH₂, —NHR or —NR₂, wherein R is alkyl.

“Cycloalkyl” means a saturated carbocyclic ring, with from three toeight carbons.

The terms “haloalkyl” and “haloalkoxy” mean alkyl or alkoxy, as the casemay be, substituted with one or more halogen atoms. The term “halogen”means F, Cl, Br or I. Preferably the halogen in a haloalkyl orhaloalkoxy is F.

The term “acyl group” means —C(O)R, wherein R is an optionallysubstituted alkyl group or aryl group (e.g., optionally substitutedphenyl). R is preferably an unsubstituted alkyl group or phenyl.

An “alkylene group” is represented by —[CH₂]_(z)—, wherein z is apositive integer, preferably from one to eight, more preferably from oneto four.

As used herein, the term “alkenyl” refers to a straight or branchedhydrocarbon group that contains one or more double bonds between carbonatoms. Suitable alkenyl groups include, e.g., n-butenyl, cyclooctenyland the like. An alkenyl group may be substituted.

The term “aryl group” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, includes carbocyclic aromaticrings and heteroaryl rings. The term “aromatic group” may be usedinterchangeably with the terms “aryl”, “aryl ring” “aromatic ring”,“aryl group” and “aromatic group”. An aromatic group typically hassix-fourteen ring atoms. A “substituted aryl group” is substituted atany one or more substitutable ring atom.

Carbocyclic aromatic rings have only carbon ring atoms (typically six tofourteen) and include monocyclic aromatic rings such as phenyl and fusedpolycyclic aromatic ring systems in which two or more carbocyclicaromatic rings are fused to one another. Examples include 1-naphthyl,2-naphthyl, 1-anthracyl.

The term “heteroaryl”, “heteroaromatic”, “heteroaryl ring”, “heteroarylgroup” and “heteroaromatic group”, used alone or as part of a largermoiety as in “heteroaralkyl” or “heteroarylalkoxy”, refers to aromaticring groups having five to fourteen ring atoms selected from carbon andat least one (typically 1-4, more typically 1 or 2) heteroatom (e.g.,oxygen, nitrogen or sulfur). They include monocyclic rings andpolycyclic rings in which a monocyclic heteroaromatic ring is fused toone or more other carbocyclic aromatic or heteroaromatic rings. Examplesof monocyclic heteroaryl groups include furanyl (e.g., 2-furanyl,3-furanyl), imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl,5-imidazolyl), isoxazolyl(e.g., 3-isoxazolyl, 4-isoxazolyl,5-isoxazolyl), oxadiazolyl (e.g., 2-oxadiazolyl, 5-oxadiazolyl),oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrazolyl (e.g.,3-pyrazolyl, 4-pyrazolyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl,3-pyrrolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl),pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl),pyridazinyl (e.g., 3-pyridazinyl), thiazolyl (e.g., 2-thiazolyl,4-thiazolyl, 5-thiazolyl), triazolyl (e.g., 2-triazolyl, 5-triazolyl),tetrazolyl (e.g., tetrazolyl) and thienyl (e.g., 2-thienyl, 3-thienyl.Examples of monocyclic six-membered nitrogen-containing heteraryl groupsinclude pyrimidinyl, pyridinyl and pyridazinyl. Examples of polycyclicaromatic heteroaryl groups include carbazolyl, benzimidazolyl,benzothienyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl,benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolinyl, indolyl,isoindolyl, acridinyl, or benzisoxazolyl.

The term “non-aromatic heterocyclic group”, used alone or as part of alarger moiety as in “non-aromatic heterocyclylalkyl group”, refers tonon-aromatic ring systems typically having five to twelve members,preferably five to seven, in which one or more ring carbons, preferablyone or two, are each replaced by a heteroatom such as N, O, or S. Anon-aromatic heterocyclic group can be monocyclic or fused bicyclic. A“nitrogen-containing non-aromatic heterocyclic group” is a non-aromaticheterocyclic group with at least one nitrogen ring atom.

Examples of non-aromatic heterocyclic groups include (tetrahydrofuranyl(e.g., 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl),[1,3]-dioxalanyl, [1,3]-dithiolanyl, [1,3]-dioxanyl, tetrahydrothienyl(e.g., 2-tetrahydrothienyl, 3-tetrahydrothieneyl), azetidinyl (e.g.,N-azetidinyl, 1-azetidinyl, 2-azetidinyl), oxazolidinyl (e.g.,N-oxazolidinyl, 2-oxazolidinyl, 4-oxazolidinyl, 5-oxazolidinyl),morpholinyl (e.g., N-morpholinyl, 2-morpholinyl, 3-morpholinyl),thiomorpholinyl (e.g., N-thiomorpholinyl, 2-thiomorpholinyl,3-thiomorpholinyl), pyrrolidinyl (e.g., N-pyrrolidinyl, 2-pyrrolidinyl,3-pyrrolidinyl)piperazinyl (e.g., N-piperazinyl, 2-piperazinyl),piperidinyl (e.g., N-piperidinyl), 2-piperidinyl, 3-piperidinyl,4-piperidinyl), thiazolidinyl (e.g., 4-thiazolidinyl), diazolonyl andN-substituted diazolonyl. The designation “N” on N-morpholinyl,N-thiomorpholinyl, N-pyrrolidinyl, N-piperazinyl, N-piperidinyl and thelike indicates that the non-aromatic heterocyclic group is attached tothe remainder of the molecule at the ring nitrogen atom.

A “substitutable ring atom” in an aromatic group is a ring carbon ornitrogen atom bonded to a hydrogen atom. The hydrogen can be optionallyreplaced with a suitable substituent group. Thus, the term“substitutable ring atom” does not include ring nitrogen or carbon atomswhich are shared when two aromatic rings are fused. In addition,“substitutable ring atom” does not include ring carbon or nitrogen atomswhen the structure depicts that they are already attached to a moietyother than hydrogen.

An aryl group may contain one or more substitutable ring atoms, eachbonded to a suitable substituent. Examples of suitable substituents on asubstitutable ring carbon atom of an aryl group include halogen, alkyl,haloalkyl, Ar^(A), —OR^(A), —O(haloalkyl), —SR^(A), —NO₂, —CN,—N(R^(B))₂, —NR^(B)C(O)R^(A), —NR^(B)CO₂R^(C), —N(R^(B))C(O)N(R^(B))₂,—C(O)R^(A), —CO₂R^(A), —S(O)₂R^(A), —SO₂N(R^(B))₂, —S(O)R^(C),—NR^(B)SO₂N(R^(B))₂, —NR^(B)SO₂R^(C), —V_(A)—Ar^(A), —V_(A)—OR^(A),—V—O(haloalkyl), —V_(A)—SR^(A), —V_(A)—NO₂, —V_(A)—CN, —V_(A)—N(R^(B))₂,—V_(A)—NR^(B)C(O)R^(A), —V_(A)—NR^(B)CO₂R^(C),—V_(A)—N(R^(B))C(O)N(R^(B))₂, —V_(A)—C(O)R^(A), —V_(A)—CO₂R^(A),—V_(A)—S(O)₂R^(A), —V_(A)—SO₂N(R^(B))₂, —V_(A)—S(O)R^(C),—V_(A)—NR^(B)SO₂N(R^(B))₂, —V_(A)—NR^(B)SO₂R^(C), —O—V_(A)—Ar^(A),—O—V_(B)—N(R^(B))₂, —S—V_(A)—Ar^(A), —S—V_(B)—N(R^(B))₂,—N(R^(B))—V_(B)—Ar^(A), —N(R^(B))—V_(B)—N(R^(B))₂,—NR^(B)C(O)—V_(A)—N(R^(B))₂, —NR^(B)C(O)—V_(A)—Ar^(A),—C(O)—V_(A)—N(R^(B))₂, —C(O)—V_(A)—Ar^(A), —CO₂—V_(B)—N(R^(B))₂,—CO₂—V_(A)—Ar^(A), —C(O)N(R^(B))—V_(B)—N(R^(B))₂,—C(O)N(R^(B))—V_(A)—Ar^(A), —S(O)₂—V_(A)—N(R^(B))₂, —S(O)₂—V_(A)—Ar^(A),—SO₂N(R^(B))—V_(B)—N(R^(B))₂, —SO₂N(R^(b))—V_(A)—Ar^(A),—S(O)—V_(A)—N(R^(B))₂, —S(O)—V_(A)—Ar^(A), —NR^(B)SO₂—V_(A)—N(R^(B))₂ or—NR^(B)SO₂—V_(A)—Ar^(A); or two adjacent substituents, taken together,form a methylenedioxy, ethylenedioxy or —[CH₂]₄— group.

Each V_(A) is independently a C1-C10 alkylene group.

Each V_(B) is independently a C2-C10 alkylene group.

Ar^(A) is a monocyclic aromatic group each substituted with zero, one ortwo groups independently selected from halogen, alkyl, amino,alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy orhaloalkyl.

Each R^(A) is independently i) hydrogen; ii) an aromatic groupsubstituted with zero, one or two groups represented by halogen, alkyl,amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy,haloalkoxy or haloalkyl; or iii) an alkyl group optionally substitutedwith halogen, hydroxyl, alkoxy, nitro, cyano, alkoxycarbonyl,alkylcarbonyl or haloalkoxy.

Each R^(B) is independently R^(A), —CO₂R^(A), —SO₂R^(A) or —C(O)R^(A);or —N(R^(B))₂ taken together is an optionally substituted non-aromaticheterocyclic group.

Each R^(C) is independently: i) an aromatic group substituted with zero,one or two groups represented by halogen, alkyl, amino, alkylamino,dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy or haloalkyl; orii) an alkyl group optionally substituted with halogen, hydroxyl,alkoxy, nitro, cyano, alkoxycarbonyl, alkylcarbonyl or haloalkoxy.

An alkyl or a non-aromatic heterocyclic group (including, but notlimited to, non-aromatic heterocyclic groups represented by —N(R³¹)₂,—N(R⁴¹)₂, —N(R⁵¹)₂ and —N(R^(B))₂) may contain one or more substituents.Examples of suitable substituents for an alkyl or a ring carbon of anon-aromatic heterocyclic group include those listed above for asubstitutable carbon of an aryl and the following: ═O, ═S, ═NNHR^(C),═NN(R^(C))₂, ═NNHC(O)R^(C), ═NNHCO₂ (alkyl), ═NNHSO₂ (alkyl), ═NR^(C),spiro cycloalkyl group, fused cycloalkyl group or a monocyclicnon-aromatic nitrogen-containing heterocyclic group attached by a ringnitrogen atom (e.g., N-piperidinyl, N-pyrrolidinyl, N-azepanyl,N-morpholinyl, N-thiomorphinyl, N-piperazinyl or N-diazepanyl group).Each R^(C) is independently selected from hydrogen, an unsubstitutedalkyl group or a substituted alkyl group. Examples of substituents onthe alkyl group represented by R^(C) include amino, alkylamino,dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy,haloalkoxy, or haloalkyl. Preferred substituents for an alkyl or a ringcarbon of a non-aromatic heterocyclic group include C1-C2 alkyl, —OH,N-pyrrolidinyl, N-piperidinyl, N-(4-alkyl)piperazinyl, N-morpholinyl orN-pyrrolyl.

Suitable substituents on the nitrogen of a non-aromatic heterocyclicgroup or heteroaryl group include —R^(D), —N(R^(D))₂, —C(O)R^(D),—CO₂R^(D), —C(O)C(O)R^(D), —C(O)CH₂C(O)R^(D), —SO₂R^(D), —SO₂N(R^(D))₂,—C(═S)N(R^(D))₂, —C(═NH)—N(R^(D))₂, and —NR^(D)SO₂R^(D); wherein R^(D)is hydrogen, an alkyl group, a substituted alkyl group, phenyl (Ph),substituted Ph, —O(Ph), substituted —O(Ph), CH₂(Ph), substitutedCH₂(Ph), or an unsubstituted heteroaryl or heterocyclic ring. Examplesof substituents on the alkyl group or the phenyl ring represented byR^(D) include amino, alkylamino, dialkylamino, aminocarbonyl, halogen,alkyl, alkylaminocarbonyl, dialkylaminocarbonyloxy, alkoxy, nitro,cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy, orhaloalkyl. Preferred substituents on a substitutable nitrogen atom of anitrogen-containing heteroaryl or nitrogen-containing non-aromaticheterocyclic group include C1-C2 alkyl, C1-C2 hydroxyalkyl, or benzyloptionally substituted with halogen, nitro, cyano, C1-C2 alkyl, C1-C2haloalkyl, C1-C2 alkoxy or C1-C2 haloalkoxy.

In some specific embodiments, non-aromatic heterocyclic groups(including, but not limited to, non-aromatic heterocyclic groupsrepresented by —N(R³¹)₂, —N(R⁴¹)₂, —N(R⁵¹)₂ and —N(R^(B))₂) eachindependently are optionally substituted with one or more substituentsselected from the group consisting of halogen, ═O, ═S, ═N(C1-C6 alkyl),C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano,(C1-C6 alkoxy)carbonyl, (C1-C6 alkyl)carbonyl, C1-C6 haloalkoxy, amino,(C1-C6 alkyl)amino and (C1-C6 dialkyl)amino. In some more specificembodiments, the non-aromatic heterocyclic groups each independently areoptionally substituted with one or more substituents selected from thegroup consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy,C1-C6 alkoxy, nitro, cyano, (C1-C6 alkoxy)carbonyl, (C1-C6alkyl)carbonyl, C1-C6 haloalkoxy, amino, (C1-C6 alkyl)amino and (C1-C6dialkyl)amino.

Inhibitors of glucosylceramide synthase can be used to treat diabetes,such as type 2 diabetes (see WO 2006/053043, the entire teachings ofwhich are incorporated herein by reference). As such, the disclosedcompounds, which are inhibitors of glucosylceramide synthase, can beused to treat diabetes, e.g., type 2 diabetes and renal hypertrophy orhyperplasia associated with diabetic nephropathy, by administration of atherapeutically effective amount of a compound of the invention to asubject in need of such treatment.

Inhibitors of glucosylceramide synthase, such as GM3 synthase, have beenshown to be useful for treating lysosomal storage diseases (see, forexample, U.S. Pat. Nos. 6,569,889; 6,255,336; 5,916,911; 5,302,609;6,660,749; 6,610,703; 5,472,969; 5,525,616, the entire teachings ofwhich are incorporated herein by reference). As such, the disclosedcompounds, which are inhibitors of glucosylceramide synthase, can beused to treat lysosomal storage diseases, such as Tay-Sachs, Gaucher'sor Fabry's disease, by administration of a therapeutically effectiveamount of a compound of the invention to a subject in need of suchtreatment.

In an alternative embodiment of the present invention, the compounds ofthe present invention can be used for: treating disorders involving cellgrowth and division, including cancer, collagen vascular diseases,atherosclerosis, and the renal hypertrophy of diabetic patients (seeU.S. Pat. Nos. 6,916,802 and 5,849,326, the entire teachings of whichare incorporated herein by reference); inhibiting the growth of arterialepithelial cells (see U.S. Pat. Nos. 6,916,802 and 5,849,326); treatingpatients suffering from infections (see Svensson, M. et al., “EpithelialGlucosphingolipid Expression as a Determinant of Bacterial Adherence andCytokine Production,” Infect. and Immun., 62:4404-4410 (1994), theentire teachings of which are incorporated herein by reference);preventing the host, i.e., patient, from generating antibodies againstthe tumor (see Inokuchi, J. et al., “Antitumor Activity in Mice of anInhibitor of Glycosphingolipid Biosynthesis,” Cancer Lett., 38:23-30(1987), the entire teachings of which are incorporated herein byreference); and treating tumors (see Hakomori, S. “New Directions inCancer Therapy Based on Aberrant Expression of Glycosphingolipids:Anti-adhesion and Ortho-Signaling Therapy,” Cancer Cells 3:461-470(1991), Inokuchi, J. et al., “Inhibition of Experimental Metastasis ofMurine Lewis Long Carcinoma by an Inhibitor of Glucosylceramide Synthaseand its Possible Mechanism of Action,” Cancer Res., 50:6731-6737 (1990)and Ziche, M. et al., “Angiogenesis Can Be Stimulated or Repressed in InVivo by a Change in GM3:GD3 Ganglioside Ratio,” Lab. Invest., 67:711-715(1992), the entire teachings of which are incorporated herein byreference).

In an alternative embodiment, the compounds of the invention can be usedfor a vaccine-like preparation (see, for example, U.S. Pat. Nos.6,569,889; 6,255,336; 5,916,911; 5,302,609; 6,660,749; 6,610,703;5,472,969; 5,525,616). Here, cancer cells are removed from the patient(preferably as completely as possible), and the cells are grown inculture in order to obtain a large number of the cancer cells. The cellsare then exposed to the inhibitor for a time sufficient to deplete thecells of their GSLs (generally 1 to 5 days) and are reinjected into thepatient. These reinjected cells act like antigens and are destroyed bythe patient's immunodefense system. The remaining cancer cells (whichcould not be physically removed) will also be attacked by the patient'simmunodefense system. In a preferred embodiment, the patient'scirculating gangliosides in the plasma are removed by-plasmapheresis,since the circulating gangliosides would tend to block the immunodefensesystem.

As used herein a subject is a mammal, preferably a human, but can alsobe an animal in need of veterinary treatment, such as a companion animal(e.g., dogs, cats, and the like), a farm animal (e.g., cows, sheep,pigs, horses, and the like) or a laboratory animal (e.g., rats, mice,guinea pigs, and the like). Subject and patient are usedinterchangeably. A subject “in need of treatment” includes a subjectwith chronic renal failure.

“Treatment” or “treating” refers to both therapeutic and prophylactictreatment.

An “effective amount” of a pharmaceutical composition disclosed above isa quantity that results in a beneficial clinical outcome of or exerts aninfluence on, the condition being treated with the pharmaceuticalcomposition compared with the absence of treatment. The administeringamount of a pharmaceutical composition disclosed above to the subjectwill depend on the degree, severity, and type of the disease orcondition, the amount of therapy desired, and the releasecharacteristics of the pharmaceutical composition. It will also dependon the subject's health, size, weight, age, sex, and tolerance to drugs.Typically, the pharmaceutical compositions of the invention areadministered for a sufficient period of time to achieve the desiredtherapeutic effect. Dosages may range from 0.1 to 500 mg/kg body weightper day. In one embodiment, the dosing range is 1-20 mg/kg/day. Thecompound of the invention may be administered continuously or atspecific timed intervals. For example, the compound of the invention maybe administered 1, 2, 3, or 4 times per day, such as, e.g., a daily ortwice-daily formulation. Commercially available assays may be employedto determine optimal dose ranges and/or schedules for administration.For example, assays for measuring blood glucose levels are commerciallyavailable (e.g., OneTouch® Ultra®, Lifescan, Inc. Milpitas, Calif.).Kits to measure human insulin levels are also commercially available(Linco Research, Inc. St. Charles, Mo.). Additionally, effective dosesmay be extrapolated from dose-response curves obtained from animalmodels (see, e.g., Comuzzie et al., Obes. Res. 11 (1):75 (2003); Rubinoet al., Ann. Surg. 240(2):389 (2004); Gill-Randall et al., Diabet. Med.21 (7):759 (2004), the entire teachings of which are incorporated hereinby reference). Therapeutically effective dosages achieved in one animalmodel can be converted for use in another animal, including humans,using conversion factors known in the art (see, e.g., Freireich et al.,Cancer Chemother. Reports 50(4):219 (1996), the entire teachings ofwhich are incorporated herein by reference) and Table A below forequivalent surface area dosage factors.

Mouse Rat Monkey Dog Human From: (20 g) (150 g) (3.5 kg) (8 kg) (60 kg)To: Mouse 1 ½ ¼ ⅙ 1/12 To: Rat 2 1 ½ ¼ 1/7 To: Monkey 4 2 1 ⅗ ⅓ To: Dog6 4 ⅗ 1 ½ To: Human 12 7 3 2 1

Typically, the pharmaceutical compositions of the invention can beadministered before or after a meal, or with a meal. As used herein,“before” or “after” a meal is typically within two hours, preferablywithin one hour, more preferably within thirty minutes, most preferablywithin ten minutes of commencing or finishing a meal, respectively.

In one embodiment, the method of the present invention is a mono-therapywhere the pharmaceutical compositions of the invention are administeredalone. Accordingly, in this embodiment, the compound of the invention isthe only pharmaceutically active ingredient in the pharmaceuticalcompositions.

In another embodiment, the method of the invention is a co-therapy withother therapeutically active drugs known in the art for treating thedesired diseases or indications, such as one or more known drugs fortreating, diabetes, lysosomal diseases, tumors, etc.

In a particular embodiment, the method of the invention is a combinationtherapy for treating diabetes, such as Type 2 diabetes. The combinationtherapy comprise any of the compounds of the invention described hereinand at least one other compound suitable for treating diabetes. Examplesof drugs or compounds used to treat type 2 diabetes include: insulin(e.g., Novolin®, Novolog®, Velosulin®); sulfonylureas (e.g., Diabinese®,Glucotrol®, Glucotrol XL®, (Diabeta®, Amaryl®, Orinase®, Tolinase®,Micronase® and Glynase®); metformin; [alpha]-glucosidase inhibitors(e.g., Glyset®); thiazolidinediones (e.g., Actos® and Avandia®);nateglinide (Starlix®); repaglinide (Prandin®) and combination drugssuch as Avandamet® (Avandia® and metformin).

The pharmaceutical compositions of the invention optionally include oneor more pharmaceutically acceptable carriers and/or diluents therefor,such as lactose, starch, cellulose and dextrose. Other excipients, suchas flavoring agents; sweeteners; and preservatives, such as methyl,ethyl, propyl and butyl parabens, can also be included. More completelistings of suitable excipients can be found in the Handbook ofPharmaceutical Excipients (5^(th) Ed., Pharmaceutical Press (2005)).

The carriers, diluents and/or excipients are “acceptable” in the senseof being compatible with the other ingredients of the pharmaceuticalcomposition and not deleterious to the recipient thereof. Thepharmaceutical compositions can conveniently be presented in unit dosageform and can be prepared by any suitable method known to the skilledartisan. In general, the pharmaceutical compositions are prepared byuniformly and intimately bringing into association the compoundsdisclosed herein with the carriers, diluents and/or excipients and then,if necessary, dividing the product into unit dosages thereof.

The pharmaceutical compositions of the invention can be formulated as atablet, sachet, slurry, food formulation, troche, capsule, elixir,suspension, syrup, wafer, chewing gum or lozenge. A syrup formulationwill generally consist of a suspension or solution of the compounds ofthe invention described herein or salt in a liquid carrier, for example,ethanol, glycerine or water, with a flavoring or coloring agent. Wherethe composition is in the form of a tablet, one or more pharmaceuticalcarriers routinely used for preparing solid formulations can beemployed. Examples of such carriers include magnesium stearate, starch,lactose and sucrose. Where the composition is in the form of a capsule,the use of routine encapsulation is generally suitable, for example,using the aforementioned carriers in a hard gelatin capsule shell. Wherethe composition is in the form of a soft gelatin shell capsule,pharmaceutical carriers routinely used for preparing dispersions orsuspensions can be considered, for example, aqueous gums, celluloses,silicates or oils, and are incorporated in a soft gelatin capsule shell.

Though the above description is directed toward routes of oraladministration of pharmaceutical compositions consistent withembodiments of the invention, it is understood by those skilled in theart that other modes of administration using vehicles or carriersconventionally employed and which are inert with respect to thecompounds of the invention may be utilized for preparing andadministering the pharmaceutical compositions. For example, thepharmaceutical compositions of the invention may also be formulated forrectal administration as a suppository or retention enema, e.g.,containing conventional suppository bases such as cocoa butter or otherglycerides. Also, the pharmaceutical compositions of the invention canbe formulated for injection, or for transdermal or transmucosaladministration. Illustrative of various modes of administration methods,vehicles and carriers are those described, for example, in Remington'sPharmaceutical Sciences, 18^(th) ed. (1990), the disclosure of which isincorporated herein by reference.

The invention is illustrated by the following examples which are notintended to be limiting in any way.

EXEMPLIFICATION Example 1 General Methods for the Preparation ofCompounds of the Invention

A general method for the synthesis of final compounds is depicted inScheme 1. A general method for the preparation of the compounds of theinvention involves the reaction of the amine of type EVII with theappropriate reagent. The amine type EVII, such as(1R,2R)-2-amino-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-3-(pyrrolidin-1-yl)propan-1-ol, can be prepared according to the preparation ofintermediate 4 of U.S. Pat. No. 6,855,830 (the entire teachings of whichare incorporated herein by reference), or by using the general syntheticprocedures depicted in schemes 2-5. Final amide compounds, EIX can beprepared by reaction of the amine EVII with the corresponding acylatingagent using standard reaction conditions for the formation of an amide.The urea compounds, EIIX can be prepared by reaction of the amine EVIIwith the corresponding isocyanate. The carbamates, EX can be prepared byreaction of the amine EVII with the corresponding chloroformate.

Example 1A Synthesis of the Compounds of the Invention General Methodsfor the Preparation of Amide Analogs

Method 1

A mixture of Compound EVII (1 mmol), such as(1R,2R)-2-amino-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-3-(pyrrolidin-1-yl)propan-1-ol,prepared according to the preparation of intermediate 4 of U.S. Pat. No.6,855,830 (the entire teachings of which are incorporated herein byreference) or using the methods depicted in schemes 2, 3, 4 and 5, anacid (1.2 mmol), DCC (dicyclohexylcarbodiimide, 1.2 mmol) and HOBT(1-hydroxy benzotriazole, 1.2 mmol) was dissolved in CH₂Cl₂ (5 ml). Themixture was stirred at room temperature and monitored by TLC (thinliquid chromatography) for completion. After completion the mixture wasfiltered and purified by column chromatography using, for example, amixture of (CH₂Cl₂/MeOH/NH₄OH).

Method 2

A mixture of Compound EVII (1 mmol), such as(1R,2R)-2-amino-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-3-(pyrrolidin-1-yl)propan-1-ol,prepared according to the preparation of intermediate 4 of U.S. Pat. No.6,855,830 (the entire teachings of which are incorporated herein byreference) or using the methods depicted in schemes 2, 3, 4 and 5, anacid and DCC (dicyclohexylcarbodiimide, 1.2 mmol) was dissolved in CHCl₃(5 ml). The mixture was placed in the microwave reactor (T=120° C.,time=1 min) and it was then filtered and purified by columnchromatography using, for example, a mixture of (CH₂Cl₂/MeOHNH₄OH).

Method 3

A mixture of Compound EVII (1 mmol), such as(1R,2R)-2-amino-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-3-(pyrrolidin-1-yl)propan-1-ol,prepared according to the preparation of intermediate 4 of U.S. Pat. No.6,855,830 (the entire teachings of which are incorporated herein byreference) or using the methods depicted in schemes 2, 3, 4 and 5, anacid chloride (1.2 mmol) and K₂CO₃ (2 mmol) was suspended in THF (5 ml).The mixture was stirred at room temperature and monitored by TLC forcompletion. After completion, the mixture was filtered and purified bycolumn chromatography using, for example, a mixture of(CH₂Cl₂/MeOH/NH₄OH).

Method 4

Compound EVII such as(1R,2R)-2-amino-1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3-pyrrolidin-1-yl-propan-1-ol,prepared according to the preparation of intermediate 4 of U.S. Pat. No.6,855,830 (the entire teachings of which are incorporated herein byreference) or using the methods depicted in schemes 2, 3, 4 and 5, wascoupled with a variety of N-hydroxysuccinamide esters in methylenechloride under an atmosphere of nitrogen, for example, for 18 to 24hours depending on the ester used.

Preparation of N-hydroxysuccinamide Esters

Various mono- and di-keto acids were coupled with N-hydroxysuccinamidein the presence of N,N¹-dicyclohexylcarbodiimide in ethyl acetate underan atmosphere of nitrogen for 18 hours. The products were filtered toremove the dicyclohexylurea. The identity of these esters was confirmedby ¹H NMR and the crude material was then used in the preparation ofamide analogs without further purification.

Example 1B Alternative Synthetic Method for the Preparation ofIntermediate EVII Synthetic Route 1

An alternative general synthesis of Compound EVII is depicted in Scheme2. Treatment of (R)-2-(benzyloxycarbonylamino)-3-hydroxypropanoic acidwith EDCI and N,O-dimethylhydroxyamine gave the weinreb amide EI inexcellent yield. The primary alcohol was protected as the TBDMS etherEII in excellent yield by reaction with TBDMSCl in DMF. Reaction of EIIwith a grignard at low temperature gave EIII in good to excellentyields. Steroselective reduction of EIII and with L-selectride at −70 Cgave EIV in good to excellent yield and selectivity. Compound EV wasobtained in good to excellent yields after deprotection with aceticacid. Reaction with mesylate chloride and a suitable amine produced EVIin good to excellent yield. Finally, deprotection to the primary amineEVII was done in the microwave oven using NaOH aqueous solution inmethanol at 150° C. for one to three minutes depending on the specificcompound.

Example 1B Alternative Synthetic Method for the Preparation ofIntermediate EVII Synthetic Route 2

An alternative general synthesis of Compound EVII is depicted in Scheme3. Intermediate AI was obtained with excellent diastereoselectivity(96:4) by reduction of compound A with LiAlH₄ followed by reaction withan aldehyde in the presence of CuI and Me₂S. Mesylate intermediate AIIIwas obtained by reaction with Amberlyst 15 followed by reaction withMsCl in pyridine. The final compound EVII was obtained by reaction withpyrrolidine and removal of the CBz by hydrogenation.

Example 1B Alternative Synthetic Method for the Preparation ofIntermediate EVII Synthetic Route 3

A general alternative route for synthesis of compound EVII is depictedin Scheme 4. Intermediate EIV was obtain as shown in Scheme 4 was cycledinto oxazolidinone B using sodium hydride in a DMF/THF solution.Deprotection of the primary alcohol by reaction with nBu₄NF, followed byformation of the tosylate by reaction with tosyl chloride in pyridine,finally, displacement of the tosylate by an appropriate amine affordedcompound B1 in good to excellent yield. Hydrolysis of the oxazolidinonewith LiOH in a water ethanol mixture gave compound EVII.

Example 1B Alternative Synthetic Method for the Preparation ofIntermediate EVII Synthetic Route 4

An alternative general synthesis of Compound EVII is depicted in Scheme5. An aldehyde (2 equiv) is condensed with the chiral morpholinone intoluene with removal of water to provide the fused cycloadduct 2.Treatment of 2 with hydrogen chloride in an alcohol solvent such asmethanol provides amino acid 3. Removal of the N-benzyl functionalitycan be accomplished with hydrogen in the presence of a palladiumcatalyst to afford 4. Cyclization of 4 with triphosgene and baseprovides ester 5. The ester functionality can be reduced with sodiumborohydride, and the resulting alcohol converted to an appropriateleaving group (i.e. tosylate or iodide). Reaction of 6 with a suitableamine in the presence of excess base (e.g. K₂CO₃) in a polar solvent(e.g. DMSO or CH₃CN) affords 7. Final deprotection under basicconditions affords Compound EVII analogs suitable for conversion to thedesired amide final products.

Example 1C Preparation of Compound EVII Using Scheme 2 Preparation ofEII (R)-benzyl3,8,8,9,9-pentamethyl-4-oxo-2,7-dioxa-3-aza-8-siladecan-5-ylcarbamate

Imidazole (1.8 g, 26.5 mmol) was added to a solution of (R)-benzyl3-hydroxy-1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (3 g, 10.6mmol) in DMF (dimethyl formamide, 15 mL) followed by TBDMSiCl(tert-butyldimethylsilyl chloride, 2.4 g, 15.95 mmol). The reactionstirred for 12 hrs at room temperature under nitrogen atmosphere and wasquenched with aqueous ammonium chloride (100 ml). The aqueous layer wasextracted with methylene chloride (200 mL) and ethyl acetate (100 mL)and the organic layers were washed with brine and concentrated. Thecrude product was purified by column chromatography using 10% EtOAc(ethylacetate)-hexanes to give an oil (3 g, 74% yield). ¹H NMR (400 MHz,CDCl₃) δ=0 (s, 6H), 0.9 (s, 9H), 3.2 (s, 3H), 3.8 (s, 3H), 3.8-3.9 (m,2H), 4.8 (broad s, 1H), 5.1 (q, 2H), 5.7 (d, 1H), 7.2-7.4 (m, 5H).

Preparation of EIII (R)-benzyl3-(tert-butyldimethylsilyloxy)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-oxopropan-2-ylcarbamate

(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)magnesium bromide (26 g, 78 mmol)dissolved in 40 mL of THF (tetrahydrofuran) under a nitrogen atmospherewas cooled down to −70° C. and (R)-benzyl3,8,8,9,9-pentamethyl-4-oxo-2,7-dioxa-3-aza-8-siladecan-5-ylcarbamate(12.3 g, 31 mmol) dissolved in THF (13 ml) were added dropwise. Thereaction mixture was allowed to warm up to −15° C. and left to react for12 hrs followed by stirring at room temperature for 2 hrs. After coolingthe reaction mixture to −40° C. it was quenched using aqueous ammoniumchloride and the aqueous layer was extracted with EtOAc dried overmagnesium sulfate and concentrated. The crude product was purified bycolumn chromatography using 25% EtOAc-hexanes to give pure product (13g, 88% yield). ¹H NMR (400 MHz, CDCl₃) δ=0 (d, 6H), 0.9 (s, 9H), 4.0-4.2(m, 2H), 4.4 (s, 2H), 4.5 (s, 2H), 5.2 (s, 2H), 5.4 (m, 1H), 6.1 (d,1H), 7 (d, 1H), 7.4-7.7 (m, 7H).

Preparation of EIV Benzyl(1R,2R)-3-(tert-butyldimethylsilyloxy)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxypropan-2-ylcarbamate

(R)-benzyl3-(tert-butyldimethylsilyloxy)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-oxopropan-2-ylcarbamate(3.1 g, 6.6 mmol) were dissolved in THF (25 ml) and cooled down to −70°C. under nitrogen atmosphere. L Selectride (13.2 ml of 1M solution inTHF, 13 mmol) was added dropwise while keeping the temperature at −70°C. After 1 hour, the reaction was quenched with a 1M aqueous solution ofpotassium tartrate (13 ml) and extracted with EtOAc. The organic layerwas evaporated down and the product was purified by columnchromatography using 2.5% EtOAc-2% acetone-methylene chloride. Thedesired diastereomer was obtained in 80% yield (2.5 g). ¹H NMR (400 MHz,CDCl₃) δ=0 (d, 6H), 0.9 (s, 9H), 3.5 (broad s, 1H), 3.7-3.9 (m, 2H), 4.2(s, 4H), 4.9 (broad s, 1H), 5.0 (d, 2H), 5.4 (d, 1H), 6.8 (s, 2H), 6.9(s, 1H), 7.2-7.4 (m, 5H).

Preparation of EV Benzyl(1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1,3-dihydroxypropan-2-ylcarbamate

Benzyl(1R,2R)-3-(tert-butyldimethylsilyloxy)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxypropan-2-ylcarbamate(0.5 g) was dissolved in a 4 ml mixture of Acetic acid/THF/water (3/1/1)and left to stir over night. The crude was evaporated down and theproduct azeotropically dried with EtOAc (10 ml). The crude product waspurified by column chromatography using 50% EtOAc-hexane. The pureproduct was obtained in 74% yield (0.28 g). ¹H NMR (400 MHz, CDCl₃)δ=3.4-3.8 (m, 4H), 4.1 (broad s, 4H), 4.8 (s, 1H), 4.9 (broad s, 2H),5.7 (broad s, 1H), 6.8 (s, 2H), 6.9 (s, 1H), 7.2-7.4 (m, 5H).

General Procedure for Preparation of EVI and EVII

Benzyl(1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1,3-dihydroxypropan-2-ylcarbamatewas dissolved in excess pyridine, cooled to −15° C. and one equivalentof methanosulfonyl chloride was added to the mixture. Mixture wasstirred about half an hour, and ten equivalents of the amine were added.The reaction mixture was allowed to warm up to room temperature and thenheated at 50° C. overnight. The crude was evaporated down and theproduct was purified by column chromatography using a mixture ofmethanol/methylene chloride/ammonium hydroxide. The pure compound EVIwas then de-protected by hydrolysis in the microwave, using aqueous NaOH(40% in weight)/methanol solution as solvent and heating the mixture to150° C. for about 15 minutes to give the free amines of the type EVI.The final product was purified by silica-gel column chromatography usinga mixture of methanol/methylene chloride/ammonium hydroxide.

Examples of EVII Compounds i)(1R,2R)-2-amino-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-3-morpholinopropan-1-ol

¹H NMR (400 MHz, CDCl₃) δ=2.3 (dd, 2H), 2.4 (dd, 2H), 2.5-2.6 (m, 2H),3.2 (m, 1H), 3.6-3.7 (m, 4H), 4.2 (s, 4H), 4.4 (d, 1H), 6.5-6.9 (m, 3H);MS for C₁₅H₂₂N₂O₄ m/z 294.8 [M+H].

ii)(1R,2R)-2-amino-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-3-(piperidin-1-yl)propan-1-ol

¹H NMR (400 MHz, CDCl₃) δ=1.4 (broad s, 2H), 1.7 (m, 4H), 2.2-2.6 (m,6H), 3.2 (m, 1H), 4.2 (s, 4H), 4.5 (s, 1H), 6.7-6.9 (m, 3H).

Example 1D Preparation of Substituted Phenoxy Propionic Acids Example1D1 Preparation of 3-(4-methoxyphenoxy)propionic acid i)3-(4-methoxyphenoxy)propionitrile

A 740 g (5.96 mol, 1 eq.) sample of 4-methoxyphenol was charged to a 3necked 5 L flask under nitrogen. Triton B (50 mL of a 30% wt. solutionin methanol) was charged to the flask, and stirring initiated via anoverhead stirrer. Acrylonitrile (2365 mL, 35.76 mol, 6 eq.) was thencharged to the reaction flask in a single portion, and the reactionmixture heated at 78° C. for 36 h. HPLC analysis indicated that thereaction was complete at this point. Solvents were removed via rotaryevaporation, and the resulting oil was chased with toluene to removeexcess acrylonitrile. The crude material was recrystallized from TBME(tert-butyl methyl ether) 10 volumes relative to the crude weight), anddried in a vacuum oven to give 945 g of3-(4-methoxyphenoxy)propionitrile as white crystals (Yield: 89.48%). ¹HNMR (450 MHz, CDCl₃): δ=2.72 (t, 2H; CH₂CN); δ=3.83 (s, 3H; OCH₃);δ=4.05 (t, 2H; OCH₂); δ=6.70 (m, 4H; Ar—H); ¹³C NMR (112.5 MHz, CDCl₃):δ=18.843 (CH₂CN); 55.902 (OCH₃); 63.699 (OCH₂); 114.947 (CH₃OCCH);116.183 (CH₂OCCH); 117.716 (CN); 151.983 (CH₃OC); 154.775 (CH₂OC).

ii) 3-(4-methoxyphenoxy)propionic acid

A 945 g (5.34 mol, 1 eq.) sample of 1 (3-(4-methoxyphenoxy)propionitrilewas charged to a 22 L round bottom flask equipped with an overheadstirrer under N₂. To the stirred solids, 4 L of concentrated HCl wasslowly added, followed by 2 L of H₂O. The reaction mixture was heated to100° C. for 3.5 h, at which point the reaction was complete by HPLCanalysis. The reaction was cooled to 10° C. by the addition of ice tothe reaction mixture, and was filtered. The dried solids gave 920 g ofcrude 3-(4-methoxyphenoxy)propionic acid. The crude material wasdissolved in 5 L of 6 wt. % sodium carbonate (such that pH=9), and 2 Lof DCM (dichloromethane) was added to the reaction vessel. Afterstirring thoroughly, the organic layer was separated and discarded via aseparatory funnel, and the aqueous layer charged back into the 22 Lflask. The pH of the aqueous layer was carefully adjusted to 4.0, byslow addition of 6 M HCl. The precipitated solids were filtered, anddried in a vacuum oven to give 900 g of 3-(4-methoxyphenoxy)propionicacid as a white solid (Yield: 86.04%). ¹H NMR (450 MHz, CDCl₃); δ=2.78(t, 2H; CH₂COOH); 3.70 (s, 3H; OCH₃); 4.18 (t, 2H; OCH₂); 6.78 (m, 4H;Ar—H); ¹³C NMR (112.5 MHz, CDCl₃): δ=34.703 (CH₂COOH); 55.925 (OCH₃);64.088 (OCH₂); 114.855 (CH₃OCCH); 115.984 (CH₂OCCH); 152.723 (CH₃OC);154.302 (CH₂OC); 177.386 (COOH).

Example 1D2 Preparation of 3-(4-(3-oxobutyl)phenoxy)propanoic acid

Step 1: a mixture of 4-(p-hydroxyphenol)-2-butanone (1.032 g), triton B(400 μL), acrylonitrile (4 mL) and MeOH (0.8 mL) was heated at 70° C.for 20 hours. The mixture was cooled to room temperature and the solventwas removed to dryness. 3-(4-(3-oxobutyl)phenoxy)propanenitrile wasobtained as a white solid (0.572 g) after purification by columnchromatography using ethyl acetate/hexane.

Step 2: 3-(4-(3-oxobutyl)phenoxy)propanenitrile (0.478 g) was suspendedin HCl (37%, 5 mL) and placed in the microwave reactor (T=110° C., 5min). The mixture was poured onto iced water (20 g), filtered, and thesolid was washed with water (2×5 mL). After column chromatographypurification using a mixture of methylene chloride/methanol,3-(4-(3-oxobutyl)phenoxy)propanoic acid was obtained as a white solid(0.3 g). ¹H NMR (CDCl₃, 400 mHz, ppm); 2.2 (s, 3H), 2.7 (t, 2H), 2.85(m, 4H), 4.25 (t, 2H), 6.8 (d, 2H), 7.1 (d, 2H).

Example 1D3 Preparation of 3-(4-(2-methoxyethyl)phenoxy)propanoic acid

Step 1: a mixture of 4-(2-methoxy ethyl)phenol (1.547 g, 10.3 mmol),propiolic acid tert-butyl ester (1.367 g, 10.8 mmol) and N-methylmorpholine (1.18 mL, 10.8 mmol) in CH₂Cl₂ (15 mL) was stirred at roomtemperature for 24 hours. The mixture was absorbed on SiO₂ (20 g) andpurified by column chromatography using a mixture of methylenechloride/hexane. The product was obtained as a two to one mixture of(E)/(Z)-tert-butyl 3-(4-(2-methoxyethyl)phenoxy)acrylate isomers (2.0g).

Step 2: (E)/(Z)-tert-butyl 3-(4-(2-methoxyethyl)phenoxy)acrylate (0.57g) was suspended in a mixture of THF (5 mL)/HCl (2 M, 5 mL) and placedin the microwave reactor (T=100° C., 15 sec). THF was removed by rotaryevaporation and the mixture was extracted with CH₂Cl₂ (10 mL).(E)/(Z)-3-(4-(2-methoxyethyl)phenoxy)acrylic acid was obtained as awhite solid after purification by column chromatography using a mixtureof hexane/ethyl acetate.

Step 3: (E)/(Z)-3-(4-(2-methoxyethyl)phenoxy)acrylic acid (0.3 g) wasdissolved in EtOH (10 mL) and Pd/C (5%, degussa type E101, 40 mg) wasadded. The mixture was hydrogenated at atmospheric pressure for 2 hoursand then filtered and the solvent removed to dryness. After purificationby column chromatography using a mixture of hexane/ethyl acetate,3-(4-(2-methoxyethyl)phenoxy)propanoic acid was obtained as a whitesolid (0.236 g). ¹H NMR (CDCl₃, 400 mHz, ppm); 2.85 (t, 4H), 3.35 (s,3H), 3.55 (t, 2H), 4.25 (t, 2H), 6.85 (d, 2H), 7.1 (d, 2H).

Example 1D4 Preparation of 3-(4-(3-methylbutanoyl)phenoxy)propanoic acid

Step 1: 3-phenoxypropionic acid (5.0 g, 30 mmol) was dissolved in MeOH(12 mL) and H₂SO₄ (18 M, 3 drops) was added. The mixture was place inthe microwave reactor (T: 140° C., t: 5 min). The solvent wasevaporated, the mixture was partitioned in EtOAc (30 mL) and NaOH (2N,20 mL). The organic phase was dried over MgSO₄, filtered, and evaporatedto give methyl 3-phenoxypropanoate (5.0 g, 27.7 mmol, 92.5%).

Step 2: aluminum chloride (1.1 g, 8.34 mmol) was added to a coldsolution (0° C.) solution of methyl 3-phenoxypropanoate (1.0 g, 5.56mmol) and tert-butylacetyl chloride (1.25 mL, 8.34 mmol) in CH₂Cl₂ (9mL) and the reaction mixture was stirred overnight. The mixture wasevaporated and the residue was diluted with EtOAc (30 mL) and thenwashed with water (2×20 mL). The organic phase was removed and purifiedwith silica chromatography using of a gradient hexanes/EtOAc(100:0→0:100) to give methyl 3-phenoxypropanoate (600 mg, 2.27 mmol,40%).

Step 3: a solution of methyl 3-phenoxypropanoate (200 mg, 0.76 mmol) in2 mL of HCl (37%) was placed in a microwave reactor (T: 120° C., t: 5min). The mixture was poured into iced water (2 g) and washed with EtOH(3×10 mL). The organic phase was combined and evaporated. The crudeproduct was purified with silica gel chromatography using of a gradienthexanes/EtOAc (100:0→0:100) to give3-(4-(3-methylbutanoyl)phenoxy)propanoic acid (120 mg, 0.48 mmol, 63%).

Example 2 Preparation of Compounds of the Invention

The exemplary compounds shown in Example 2 and Tables 1-3 can beprepared by following scheme 1 described above, Detailed syntheticdescription of certain compounds also are described below as examples.

Example 2E1 Preparation of Hemi-Hydrate of Compound 163N-[2-Hydroxy-2-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-pyrrolidin-1-ylmethyl-ethyl]-3-(4-methoxyphenoxy)-propionamide

Compound 163 was prepared by following Scheme 1A above.3-(4-methoxyphenoxy)propanoic acid (see Example 1D1, 34.47 g, 169 mmol,96% purity by HPLC), DCC (34.78 g, 169 mmol) and N-hydroxysuccinimide(19.33, 169 mmol) were combined as dry powders and methylene chloride(500 mL) was added. The suspension was mechanically stirred overnight,ambient temperature, under a nitrogen atmosphere. HPLC analysis showedcomplete conversion of the acid to the NHS ester (N-hydroxy succinylester). To the mixture was added(1R,2R)-2-amino-1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3-pyrrolidin-1-yl-propan-1-ol(50 g, 169 mmol) and stirring continued for 2.5 hours. HPLC showedconversion to the product and loss of both the NHS ester and step 5amine. The reaction mixture was vacuum filtered on a Büchner funnel toremove DCC urea. The solid urea was washed with 500 mL of methylenechloride. The organic layers were combined, placed in a separatoryfunnel, and treated with 500 mL of 1.0M NaOH. The layers were separated,and the cloudy organic layer was recharged into a separatory funnel andtreated with a 6% HCl solution (adjusted to pH=0.03-0.34, 100 mL ofsolution). Two clear layers formed. The resultant biphasic solution waspoured into an Erlenmeyer flask and cautiously neutralized to a pH of7.2-7.4 with a saturated solution of sodium bicarbonate (approx 200 mLof solution). The organic layer was separated from the aqueous layer,dried over sodium sulfate and evaporated to yield 83.6 g of yellow oil(theoretical yield: 77.03 g). The oil was dissolved in isopropyl alcohol(500 mL) with heating and transferred to a 1 L round bottom flaskequipped with a mechanical stirrer and heating mantel. The solution washeated to 50° C. and the mechanical stirrer was set to a rate of 53-64rpm. Tartaric acid (25.33 g, 168 mmol) was dissolved in deionized water(50 mL) and added to the stirred solution at 50° C. Once the solutionturned from milky white to clear, seed crystals were added to themixture and crystallization immediately began (temperature jumped to 56°C.). After 20 minutes, the mixture was set to cool to a temperature of35° C. (cooling took 1.15 hours). Heating was removed and the solutionwas allowed to stir for 12 hours. The resulting thick slurry wasfiltered on a Büchner funnel. Any remaining solid in the flask waswashed onto the funnel using ice-cold isopropyl alcohol (100 mL). Thematerial was transferred to a drying tray and heated to 48° C. undervacuum for 3 days (after two days the material weighed 76 g and afterthree days it weighed 69.3 g). The solid was analyzed by LC and shown tobe 98.1% pure (AUC), the residual solvent analysis showed the materialto possess 3472 ppm of isopropyl alcohol, and the DSC (differentialscanning calroimetery) showed a melting point of 134.89° C. A total of69.3 g of white solid was collected (65.7% overall yield). ¹H NMR (400MHz, CDCl₃) δ=1.8 (M, 4H), 2.4-2.6 (m, 4H), 2.6 (m, 1H), 2.85 (m, 2H),3.0 (m, 1H), 3.65 (s, 3H), 3.8 (m, 2H), 3.86 (2, 2H), 4.18 (br s, 5H),4.6 (s, 1H), 6.6-6.8 (m, 7H), 7.8 (d, 1H); MS for C₂₉H₄₀N₂O₁₃ m/z 457.3[M+H] for main peak (free-base).

Example 2E2 Preparation of Compound 247N-((1R,2R)-1-hydroxy-1-(4-methoxyphenyl)-3-(pyrrolidin-1-yl)propan-2-yl)-3-(p-tolyloxy)propanamide

Compound 247 was prepared by reaction of(1R,2R)-2-amino-1-(4-methoxyphenyl)-3-(pyrrolidin-1-yl)propan-1-ol asthe amine, prepared according to scheme 3 with3-(4-methylphenoxy)propionic acid using method 1.

Preparation of A (R)-benzyl4-formyl-2,2-dimethyloxazolidine-3-carboxylate

N,O-dimethylhydroxylamine hydrochloride (45 g, 0.46 mmol, 1.5 eq) andN-methyl morpholine (84 mL, 0.765 mol, 2.5 eq.) were added slowly to acold (−15° C.) suspension of d-CBz serine (73.0 g, 0.305 mol) in CH₂Cl₂(560 mL) keeping the temperature below −5° C. The mixture was cooledback to ˜−15° C. and EDCI (62 g, 0.323 mol, 1.05 eq) was added. Themixture was stirred for 5 hours keeping the temperature below 5° C. Thesolvent was removed by rotary evaporation and the mixture waspartitioned between HCl (1 M, 300 mL) and EtOAc (500 mL). The organiclayer was separated and washed with HCl (1 M, 2×100 mL) and then sat.NaHCO₃ (2×150 mL) The mixture was dried over MgSO₄, filtered and thenthe solvent was removed by rotary evaporation. (R)-benzyl3-hydroxy-1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate wasre-dissolved in a mixture of acetone (375 mL) and 2,2-dimethoxy propane(375 mL) and boron trifluoride ethereate (3 mL) was added. The mixturewas stirred at room temperature for 5 hours and then triethyl amine (3mL) was added. The solvent was removed to dryness and (R)-benzyl4-(methoxy(methyl)carbamoyl)-2,2-dimethyloxazolidine-3-carboxylate wasobtained as a white solid (73.0 g, 74% yield from both steps) afterpurification by column chromatography using a mixture ofhexane/EtOAc/acetone.

¹H NMR (CDCl₃, 400 mHz, ppm); 1.5 (s, 2H), 1.6 (s, 3H), 1.7 (s, 2H),1.75 (s, 3H), 3.14 (s, 3H), 3.24 (2H), 3.4 (3H), 3.76 (s, 2H), 4.0 (m,1.7H), 4.16 (m, 1H), 4.2 (m, 1.7), 4.78 (m, 1H), 4.88 (m, 0.6H), 5.06(q, 2H), 5.18 (q, 1H), 7.4 (m, 8H).

Preparation of AI (R)-benzyl4-((R)-hydroxy(4-methoxyphenyl)methyl)-2,2-dimethyloxazolidine-3-carboxylate

A solution of LiALH₄ (1 M, 20 mL, 20 mmol) was added dropwise to a cold(−15° C.) solution of (R)-benzyl4-(methoxy(methyl)carbamoyl)-2,2-dimethyloxazolidine-3-carboxylate (12.2g, 37.9 mmol) in THF (75 mL) The mixture was stirred for 30 min keepingthe temperature below 0° C. A saturated solution of KHSO₄ (100 mL) wasadded slowly to the mixture and it was warmed to room temperature. Themixture was filtered and the solvent was removed to dryness. (R)-benzyl4-formyl-2,2-dimethyloxazolidine-3-carboxylate was obtained as a clearoil (9.161 g, 92% yield) after purification by column chromatography(SiO₂, using a mixture of hexane/EtOAc).

¹H NMR (CDCl₃, 400 mHz, ppm); 1.7 (m, 6H), 4.15 (m, 2H), 4.4 (m, 1H),5.15, (s, 1H), 5.2 (m, 1H), 7.3 (m, 5H), 9.6 (m, 1H).

1,2-dibromoethane (0.2 mL) was added slowly to a hot (65° C.) solutionof magnesium turnings (0.91 g, 37 mmol) in THF (14 mL), followed by thedropwise addition of a solution of 4-bromo anisole (4 mL, 32 mmol) inTHF (14 mL). The mixture was refluxed for 2 hours and then cooled toroom temperature. The grignard solution was added dropwise to asuspension of CuI (6.8 g, 36 mmol) in a mixture of Me₂S (20 mL)/THF (100mL) at −78° C. The mixture was warmed slowly to −45° C. and stirred for30 min keeping the temperature between −45 to −35° C. The mixture wascooled back to −78° C., and a solution of the Garner's aldehyde[(R)-benzyl 4-formyl-2,2-dimethyloxazolidine-3-carboxylate] (3.20 g,12.6 mmol) in THF (15 mL) was added dropwise. The mixture was stirred atlow temperature overnight (15 h, T max=10° C.). The reaction mixture wasquenched with NH₄Cl (sat. 100 mL) and extracted with EtOAc (50 mL). Thesolvent was removed to dryness and the mixture was purified by columnchromatography (SiO₂, using a mixture of hexane/EtOAc/acetone) and theproduct was obtained as a colorless oil (1.697 g, 36% yield).

Preparation of AII benzyl(1R,2R)-1,3-dihydroxy-1-(4-methoxyphenyl)propan-2-ylcarbamate

A mixture of benzyl4-(hydroxy-(4-methoxyphenyl)methyl)-2,2-dimethyloxazolidine-3-carboxylate(1.679 g, 4.5 mmol) and amberlyst 15 (1.85 g) in MeOH (20 mL) wasstirred at room temperature for 2 days. The mixture was centrifuged andthe solid was washed with MeOH (2×40 mL). The solvent was removed todryness and after purification by column chromatography (SiO₂ using amixture of CH₂Cl₂/EtOAc) the product was obtained as a white solid (1.26g, 84% yield).

Preparation of AIV Synthesis of Compound 289 benzyl(1R,2R)-1-hydroxy-1-(4-methoxyphenyl)-3-(pyrrolidin-1-yl)propan-2-ylcarbamate

Mesityl chloride (0.28 mL, 3.6 mmol) was added slowly to a cold (−10°C.) solution of benzyl(1R,2R)-1,3-dihydroxy-1-(4-methoxyphenyl)propan-2-ylcarbamate (1.07 g,3.23 mmol) in pyridine (1.5 mL). The mixture was stirred for 30 min andthen pyrrolidine (2.7 mL, 33 mmol) was added slowly to the mixture. Themixture was heated to 45° C. for 6 hours and then the solvent wasremoved to dryness. After purification by column chromatography (SiO₂,using a mixture of CH₂Cl₂, MeOH, NH₄OH), the product was obtained as aclear oil (0.816 g, 66% yield).

Preparation of EVII

(1R,2R)-2-amino-1-(4-methoxyphenyl)-3-(pyrrolidin-1-yl)propan-1-ol asthe amine was prepared by the procedures described below:

A mixture of benzyl(1R,2R)-1-hydroxy-1-(4-methoxyphenyl)-3-(pyrrolidin-1-yl)propan-2-ylcarbamate(0.10 g, 0.26 mmol) and Pd/C (5%, 21 mg) in EtOH (1 mL)/HCl (1 M, 50 μL)was degassed and hydrogen gas was added. The mixture was hydrogenated atatmospheric pressure for two hours. The mixture was filtered over celiteand the solvent was removed to dryness. The product was obtained as acolorless oil (63.5 mg, 85% yield).

Preparation of Compound 247N-((1R,2R)-1-hydroxy-1-(4-methoxyphenyl)-3-(pyrrolidin-1-yl)propan-2-yl)-3-(p-tolyloxy)propanamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.75 (br, 4H), 2.3 (s, 3H), 2.65 (br, 6H),2.85 (m, 2H), 3.75 (s, 3H), 4.1 (m, 2H), 4.25 (m, 1H), 5.05 (sd, 1H),6.5 (br, 1H), 6.8 (m, 4H), 7.1 (d, 2H), 7.2 (d, 2H). M/Z for C₂₄H₃₂N₂O₄[M−H]⁻=413.

Example 2E3 Preparation of Compound 251N-((1R,2R)-1-hydroxy-1-(4-methoxyphenyl)-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4-(trifluoromethyl)phenyl)acetamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.75 (br, 4H), 2.55 (br, 4H), 2.85 (m,2H), 3.5 (s, 2H), 3.8 (s, 3H), 4.2 (m, 1H), 5.05 (sd, 1H), 5.8 (d, 1H),6.8 (d, 2H), 7.1 (d, 2H), 7.2 (d, 2H), 7.55 (d, 2H). M/Z forC₂₃H₂₇F₃N₂O₃ [M−H]⁻=437.

Example 2E4 Preparation of Compound 5N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)benzo[b]thiophene-2-carboxamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.8 (br, 4H), 2.7 (br, 4H), 3.0 (m, 2H),4.25 (s, 4H), 4.45 (m, 1H), 5.05 (sd, 1H), 6.6 (br, 1H), 6.85 (s, 2H),6.95 (s, 1H), 7.4 (m, 2H), 7.7 (s, 1H), 7.85 (m, 2H). M/Z forC₂₄H₂₆N₂O₄S [M−H]⁻=439.

Example 2E5 Preparation of Compound 11N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(phenylthio)acetamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.7 (br, 4H), 2.5 (br, 4H), 2.8 (br, 2H),3.6 (q, 2H), 4.1.5 (m, 1H), 4.2 (s, 4H), 5.9 (sd, 1H), 6.7 (m, 2H), 6.8(s, 1H), 7.2 (m, 7H). M/Z for C₂₃H₂₈N₂O₄S [M−H]⁻=429.

Example 2E6 Preparation of Compound 12N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)biphenyl-4-carboxamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.8 (br, 4H), 2.7 (br, 4H), 3.0 (m, 2H),4.25 (s, 4H), 4.4 (br, 1H), 5.05 (sd, 1H), 6.6 (sd, 1H), 6.85 (m, 2H),6.95 (s, 1H), 7.45 (m, 3H), 7.6 (m, 4H), 7.75 (m, 2H). M/Z forC₂₈H₃₀N₂O₄ [M−H]⁻=459.

Example 2E7 Preparation of Compound 19N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)benzo[b]thiophene-5-carboxamide

¹H NMR (d₆-dmso, 400 mHz, ppm); 1.6 (br, 4H), 2.4 (br, 5H), 2.65 (m,1H), 4.15 (s, 4H), 4.25 (m, 1H), 4.75 (sd, 1H), 5.6 (br, 1H), 6.7 (m,3H), 7.5 (sd, 1H), 7.7 (sd, 1H), 7.8 (sd, 1H), 7.85 (sd, 1H), 8.0 (sd,1H), 8.2 (s, 1H). M/Z for C₂₄H₂₆N₂O₄S [M−H]⁻=439.

Example 2E8 Preparation of Compound 232-(biphenyl-4-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.7 (br, 4H), 2.5 (br, 4H), 2.8 (d, 2H),3.55 (s, 2H), 4.2 (m, 5H), 4.85 (sd, 1H), 5.95 (br, 1H), 6.6 (m, 1H),6.75 (m, 2H), 7.2 (sd, 2H), 7.4 (m, 1H), 7.5 (st, 2H), 7.6 (m, 4H). M/Zfor C₂₉H₃₂N₂O₄ [M−H]⁻=473.

Example 2E9 Preparation of Compound 24N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4-phenoxyphenyl)acetamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.8 (br, 4H), 2.6 (br, 4H), 2.8 (sd, 2H),3.45 (s, 2H), 4.15 (m, 1H), 4.25 (s, 4H), 4.85 (sd, 1H), 5.9 (br, 1H),6.6 (m, 1H), 6.7 (s, 1H), 6.8 (m, 1H), 7.15 (m, 7H), 7.4 (m, 2H). M/Zfor C₂₉H₃₂N₂O₅ [M−H]⁻=489.

Example 2E10 Preparation of Compound 25(S)—N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-hydroxy-3-phenylpropanamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.8 (br, 4H), 2.65 (br, 7H), 3.1 (dd, 2H),4.2 (m, 6H), 4.8 (sd, 1H), 6.6 (m, 1H), 6.8 (m, 3H), 7.3 (m, 5H). M/Zfor C₂₄H₃₀N₂O₅ [M−H]⁻=427.

Example 2E11 Preparation of Compound 27N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-phenoxypropanamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.8 (br, 4H), 2.7 (br, 6H), 2.9 (m, 2H),4.2 (m, 7H), 4.95 (sd, 1H), 6.45 (m, 1H), 6.75 (s, 1H), 6.85 (m, 3H),6.95 (t, 1H), 7.2 (m, 3H). M/Z for C₂₄H₃₀N₂O₅ [M−H]⁻=427.

Example 2E12 Preparation of Compound 31N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-pyrrolidin-1-yl)propan-2-yl)-2-oxo-2-phenylacetamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.8 (br, 4H), 2.8 (br, 4H), 3.0 (m, 2H),4.2 (s, 4H), 4.3 (m, 1H), 5.05 (sd, 1H), 6.8 (s, 2H), 6.9 (s, 1H), 7.35(m, 1H), 7.45 (t, 2H), 7.6 (t, 1H) 8.2 (d, 2H). M/Z for C₂₃H₂₆N₂O₅[M−H]⁻=411.

Example 2E13 Preparation of Compound 32N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(phenylthio)propanamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.8 (br, 4H), 2.4 (t, 2H), 2.7 (br, 4H),2.8 (m, 2H), 3.1 (m, 2H), 4.2 (m, 5H), 4.9 (sd, 1H), 5.95 (br, 1H), 6.8(m, 3H), 7.2 (m, 1H), 7.3 (m, 3H). M/Z for C₂₄H₃₀N₂O₄S [M−H]⁻=443.

Example 2E14 Preparation of Compound 35N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-yl)-2-o-tolylacetamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.7 (br, 4H), 2.1 (s, 3H), 2.5 (br, 4H),2.75 (m, 2H), 3.5 (s, 2H), 4.1 (m, 1H), 4.25 (s, 4H), 4.8 (sd, 1H), 5.75(br, 1H), 6.5 (d, 1H), 6.65 (s, 1H), 6.75 (d, 1H), 7.1 (d, 1H), 7.2 (m,3H). M/Z for C₂₄H₃₀N₂O₄ [M−H]⁻=411.

Example 2E15 Preparation of Compound 36N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-m-tolylacetamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.7 (br, 4H), 2.35 (s, 3H), 2.5 (br, 4H),2.75 (m, 2H), 3.45 (s, 2H), 4.1 (m, 1H), 4.25 (s, 4H), 4.85 (sd, 1H),5.8 (br, 1H), 6.55 (d, 1H), 6.75 (m, 2H), 6.9 (d, 2H), 7.1 (sd, 1H), 7.2(m, 1H). M/Z for C₂₄H₃₀N₂O₄ [M−H]⁻=411.

Example 2E16 Preparation of Compound 392-(benzylthio)-N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.8 (br, 4H), 2.7 (br, 4H), 2.9 (m, 2H),3.0 (m, 2H), 3.3 (d, 1H), 3.55 (d, 1H), 4.2 (m, 5H), 5.05 (sd, 1H), 6.85(s, 2H), 6.9 (s, 1H), 7.1 (sd, 2H), 7.3 (m, 3H). M/Z for C₂₄H₃₀N₂O₄S[M−H]⁻=443.

Example 2E17 Preparation of Compound 47N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-pyrrolidin-1-yl)propan-2-yl)-2-(4-(pyridin-3-yl)phenyl)acetamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.7 (br, 4H), 2.6 (br, 4H), 2.8 (sd, 2H),3.55 (s, 2H), 4.15 (m, 1H), 4.2 (s, 4H), 4.85 (sd, 1H), 5.85 (br, 1H),6.6 (d, 1H), 6.75 (m, 2H), 7.25 (d, 3H), 7.4 (m, 1H), 7.6 (sd, 2H), 7.9(sd, 1H), 8.6 (sd, 1H), 8.85 (s, 1H). M/Z for C₂₈H₃₁N₃O₄ [M−H]⁻=474.

Example 2E18 Preparation of Compound 482-(4′-chlorobiphenyl-4-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.75 (br, 4H), 2.55 (br, 4H), 2.8 (sd,2H), 3.55 (s, 2H), 4.15 (m, 1H), 4.2 (s, 4H), 4.85 (sd, 1H), 5.8 (br,1H), 6.6 (d, 1H), 6.75 (m, 2H), 7.2 (d, 2H), 7.4 (m, 2H), 7.55 (sd, 4H).M/Z for C₂₉H₃₁ClN₂O₄ [M−H]⁻=508.

Example 2E19 Preparation of Compound 51N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(3-(trifluoromethyl)phenyl)acetamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.7 (br, 4H), 2.55 (br, 4H), 2.8 (sd, 2H),3.55 (s, 2H), 4.15 (m, 1H), 4.25 (s, 4H), 4.85 (sd, 1H), 5.8 (br, 1H),6.6 (d, 1H), 6.75 (m, 2H), 7.35 (d, 1H), 7.45 (m, 2H), 7.55 (sd, 1H).M/Z for C₂₄H₂₇F₃N₂O₄ [M−H]⁻=465.

Example 2E20 Preparation of Compound 53N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(3-fluorophenyl)acetamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.7 (br, 4H), 2.55 (br, 4H), 2.8 (sd, 2H),3.50 (s, 2H), 4.15 (m, 1H), 4.25 (s, 4H), 4.85 (sd, 1H), 5.8 (br, 1H),6.6 (d, 1H), 6.75 (m, 1H), 6.8 (d, 1H), 6.85 (d, 1H), 6.9 (d, 1H), 7.0(t, 1H), 7.3 (sq, 1H). M/Z for C₂₃H₂₇FN₂O₄ [M−H]⁻=415.

Example 2E21 Preparation of Compound 54N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(3-methoxyphenoxy)propanamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.7 (br, 4H), 2.65 (br, 6H), 2.85 (m, 2H),3.80 (s, 3H), 4.2 (m, 7H), 4.95 (sd, 1H), 6.45 (m, 4H), 6.75 (s, 2H),6.85 (s, 1H), 7.2 (t, 1H). M/Z for C₂₅H₃₂N₂O₆ [M−H]⁻=457.

Example 2E22 Preparation of Compound 553-(2,5-dichlorophenoxy)-N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)propanamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.8 (br, 4H), 2.65 (br, 6H), 2.8 (m, 2H),4.1 (m, 1H), 4.25 (m, 6H), 4.95 (sd, 1H), 6.3 (br, 1H), 6.75 (s, 2H),6.8 (s, 1H), 6.9 (m, 2H), 7.25 (m, 1H). M/Z for C₂₄H₂₈Cl₂N₂O₅[M−H]⁻=496.

Example 2E23 Preparation of Compound 573-(4-chlorophenoxy)-N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)propanamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.75 (br, 4H), 2.65 (br, 6H), 2.8 (m, 2H),4.2 (m, 7H), 4.95 (sd, 1H), 6.3 (br, 1H), 6.8 (m, 5H), 7.2 (m, 2H). M/Zfor C₂₄H₂₉ClN₂O₅ [M−H]⁻=461.

Example 2E24 Preparation of Compound 58N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(4-fluorophenoxy)propanamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.75 (br, 4H), 2.65 (br, 6H), 2.8 (m, 2H),4.2 (m, 7H), 4.95 (sd, 1H), 6.4 (br, 1H), 6.8 (m, 5H), 7.0 (m, 2H). M/Zfor C₂₄H₂₉FN₂O₅ [M−H]⁻=445.

Example 2E25 Preparation of Compound 59N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(p-tolyloxy)propanamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.75 (br, 4H), 2.3 (s, 3H), 2.65 (br, 6H),2.8 (m, 2H), 4.2 (m, 7H), 4.95 (sd, 1H), 6.45 (br, 1H), 6.75 (m, 4H),6.85 (s, 1H), 7.1 (m, 2H). M/Z for C₂₅H₃₂N₂O₅ [M−H]⁻=441.

Example 2E26 Preparation of Compound 60N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(2-fluorophenoxy)propanamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.75 (br, 4H), 2.65 (br, 6H), 2.75 (m,2H), 4.2 (m, 7H), 4.95 (sd, 1H), 6.35 (br, 1H), 6.7 (s, 2H), 6.85 (s,1H), 6.95 (m, 2H), 7.05 (m, 2H). M/Z for C₂₄H₂₉FN₂O₅ [M−H]⁻=445.

Example 2E27 Preparation of Compound 61N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(4-methoxyphenoxy)propanamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.75 (br, 4H), 2.65 (br, 6H), 2.75 (m,2H), 3.8 (s, 3H), 4.1 (m, 2H), 4.2 (br, 5H), 4.95 (sd, 1H), 6.45 (br,1H), 6.8 (m, 7H). M/Z for C₂₅H₃₂N₂O₆ [M−H]⁻=457.

Example 2E28 Preparation of Compound 188N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(4-ethylphenoxy)propanamide(2R,3R)-2,3-dihydroxysuccinate

¹H NMR (D₂O, 400 mHz, ppm); 0.93 (t, 3H), 1.75 (br, 2H), 1.86 (br, 2H),2.35 (q, 2H), 2.4 (br, 2H), 2.9 (br, 2H), 3.25 (m, 2H), 3.4 (br, 2H),3.9 (br, 6H), 4.3 (br, 3H), 4.6 (br, 1H), 6.6 (m, 5H), 7.0 (d, 2H). M/Zfor C₂₆H₃₄N₂O₅.C₄H₆O₆ [M−H]⁻=454.

Example 2E29 Preparation of Compound 189N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(4-propionylphenoxy)propanamide(2R,3R)-2,3-dihydroxysuccinate

¹H NMR (D₂O, 400 mHz, ppm); 0.93 (t, 3H), 1.75 (br, 2H), 1.86 (br, 2H),2.45 (br, 2H), 2.8 (q, 2H), 2.9 (br, 2H), 3.25 (m, 2H), 3.4 (br, 2H),3.9 (br, 6H), 4.3 (br, 3H), 4.6 (br, 1H), 6.5 (d, 1H), 6.5 (d, 2H), 6.7(d, 2H), 7.7 (d, 2H). M/Z for C₂₇H₃₄N₂O₆.C₄H₆O₆ [M−H]⁻=483.

Example 2E30 Preparation of Compound 193N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(4-(3-oxobutyl)phenoxy)propanamide(2R,3R)-2,3-dihydroxysuccinate

¹H NMR (D₂O, 400 mHz, ppm); 1.75 (br, 2H), 1.86 (br, 2H), 1.94 (s, 3H),2.45 (br, 2H), 2.6 (m, 4H), 2.9 (br, 2H), 3.25 (m, 2H), 3.4 (br, 2H),3.9 (br, 6H), 4.3 (br, 3H), 4.6 (br, 1H), 6.6 (m, 5H), 7.0 (d, 2H). M/Zfor C₂₈H₃₆N₂O₆.C₄H₆O₆ [M−H]⁻=497.

Example 2E31 Preparation of Compound 202N-((1R,R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(4-(2-methoxyethyl)phenoxy)propanamide(2R,R)-2,3-dihydroxysuccinate

¹H NMR (D₂O, 400 mHz, ppm); 1.75 (br, 2H), 1.86 (br, 2H), 2.45 (br, 2H),2.62 (t, 2H), 2.9 (br, 2H), 3.1 (s, 3H), 3.25 (m, 2H), 3.4 (br, 4H), 3.9(br, 6H), 4.3 (br, 3H), 4.6 (br, 1H), 6.6 (m, 5H), 7.0 (d, 2H). M/Z forC₂₇H₃₆N₂O₆.C₄H₆O₆ [M−H]⁻=485.

Example 2E32 Preparation of Compound 63N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(3′-methoxybiphenyl-4-yl)acetamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.7 (br, 4H), 2.5 (br, 4H), 2.75 (m, 2H),3.5 (br, 2H), 3.9 (sd, 3H), 4.2 (m, 5H), 4.95 (sd, 1H), 5.9 (br, 1H),6.5-7.6 (m, 11H). M/Z for C₃₀H₃₄N₂O₅ [M−H]⁻=503.

Example 2E33 Preparation of Compound 127N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-4-(4-ethoxyphenyl)-4-oxobutanamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.4 (t, 3H), 1.8 (br, 4H), 2.7 (br, 6H),3.2 (m, 2H), 4.05 (q, 2H), 4.2 (m, 2H), 4.25 (m, 5H), 4.95 (sd, 1H),6.05 (br, 1H), 6.9 (m, 5H), 7.95 (d, 2H). M/Z for C₂₇H₃₄N₂O₆ [M−H]⁻=483.

Example 2E34 Preparation of Compound 154N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-pyrrolidin-1-yl)propan-2-yl)-4-(4-methoxyphenyl)-4-oxobutanamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.8 (br, 4H), 2.7 (br, 6H), 3.2 (m, 1H),3.45 (s, 3H), 3.9 (s, 3H), 4.2 (m, 5H), 4.95 (sd, 1H), 6.05 (br, 1H),6.9 (m, 5H), 7.95 (d, 2H). M/Z for C₂₆H₃₂N₂O₆ [M−H]⁻=469.

Example 2E35 Preparation of Compound 181N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-6-(4-isopropoxyphenyl)-6-oxohexanamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.4 (d, 6H), 1.8 (br, 8H), 2.15 (br, 2H),2.8 (br, 10H), 4.25 (m, 5H), 4.65 (m, 1H), 4.95 (sd, 1H), 6.05 (br, 1H),6.9 (m, 5H), 7.95 (d, 2H). M/Z for C₃₀H₄₀N₂O₆ [M−H]⁻=525.

Example 2E36 Preparation of Compound 191N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-5-(4-methoxyphenyl)-5-oxopentanamide(2R,3R)-2,3-dihydroxysuccinate

¹H NMR (D₂O, 400 mHz, ppm); 1.40 (br, 1H), 1.53 (br, 1H), 1.75 (br, 2H),1.91 (br, 2H), 1.98 (m, 1H), 2.15 (m, 1H), 2.45 (m, 2H), 2.95 (m, 2H),3.35 (dd, 2H), 3.4 (m, 2H), 3.68 (br, 5H), 3.77 (br, 2H), 4.3 (br, 3H),4.68 (br, 1H), 6.47 (d, 1H), 6.65 (d, 2H), 6.85 (d, 2H), 7.63 (d, 2H).M/Z for C₂₇H₃₄N₂O₆.C₄H₆O₆ [M−H]=483.

Example 2E37 Preparation of Compound 265N-((1R,2R)-1-(benzo[δ][1,3]dioxol-5-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-5-(4-isopropoxyphenyl)-5-oxopentanamide(2S,3S)-2,3-dihydroxysuccinate

¹H NMR (400 MHz, CD₃OD) δ 1.30 (sd, 6H), 1.70-1.85 (m, 2H), 2.04 (br,4H), 2.09-2.26 (m, 2H), 2.64-2.82 (m, 2H), 3.31-3.48 (m, 5H), 4.37 (s,2H), 4.43 (br, 1H), 4.68 (m, 1H), 4.71 (sd, 1H), 5.76 (s, 2H), 6.66 (d,1H), 6.82-6.95 (m, 4H), 7.84 (d, 2H); MS for C₂₈H₃₆N₂O₆.C₄H₆O₆: [M−H]⁻645.

Example 2E38 Preparation of Compound 267N-((1R,2R)-1-(benzo[δ][1,3]-dioxol-5-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-6-(4-methoxyphenyl)-6-oxohexanamide(2S,3S)-2,3-dihydroxysuccinate

¹H NMR (400 MHz, CD₃OD) δ 1.49 (br, 4H), 2.03 (br, 4H), 2.89 (t, 2H),3.33-3.46 (m, 6H), 3.84 (s, 3H), 4.37 (s, 2H), 4.43 (d, 1H), 4.76 (br,1H), 5.81 (s, 2H), 6.68 (d, 1H), 6.81 (d, 1H), 6.88 (s, 1H), 6.96 (d,2H), 7.92 (d, 2H); MS for C₂₇H₃₄N₂O₆.C₄H₆O₆: [M−H]⁻ 633.

Example 2E39 Preparation of Compound 268N-((1R,2R)-1-(benzo[δ][1,3]dioxol-5-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-7-(4-isopropoxyphenyl)-7-oxoheptanamide(2S,3S)-2,3-dihydroxysuccinate

¹H NMR (400 MHz, CD₃OD) δ 1.15-1.18 (m, 2H), 1.30 (d, 6H), 1.40-1.45 (m,2H), 1.57-1.65 (m, 2H), 2.03 (br, 4H), 2.12-2.17 (m, 2H), 2.88 (t, 2H),3.33-3.48 (m, 5H), 4.38 (s, 2H), 4.42 (d, 1H), 4.67 (m, 1H), 4.78 (d,1H), 5.83 (d, 2H), 6.71 (d, 1H), 6.82 (d, 1H), 6.89 (s, 1H), 6.92 (d,2H), 7.90 (d, 2H); MS for C₃₀H₄₀N₂O₆.C₄H₆O₆: [M−H]⁻ 675.

Example 2E40 Preparation of Compound 197N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-4-(4-methoxyphenoxy)butanamide(2S,3S)-2,3-dihydroxysuccinate

¹H NMR (400 MHz, CD₃OD) δ 1.78-1.91 (m, 2H), 2.00 (br, 4H), 2.32 (t,2H), 3.33-3.47 (m, 6H), 3.69 (s, 3H), 3.72 (t, 2H), 4.11 (br, 4H), 4.37(s, 2H), 4.41 (d, 1H), 4.72 (d, 1H), 6.69-6.86 (m, 7H); MS forC₂₆H₃₄N₂O₆.C₄H₆O₆: [M−H]⁻ 621.

Example 2E41 Preparation of Compound 187N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(4-(3-methylbutanoyl)phenoxy)propanamide(2S,3S)-2,3-dihydroxysuccinate

¹H NMR (400 MHz, CD₃OD) δ 0.95 (d, 6H), 2.00 (br, 4H), 2.17 (m, 2H),2.66 (t, 2H), 2.78 (d, 2H), 3.34-3.44 (m, 5H), 4.12-4.17 (m, 6H), 4.40(s, 2H), 4.45 (d, 1H), 4.73 (sd, 1H), 6.67 (d, 1H), 6.79 (d, 1H), 6.86(s, 1H), 6.93 (d, 2H), 7.91 (d, 2H); MS for C₂₉H₃₈N₂O₆.C₄H₆O₆: [M−H]⁻661.

Example 2E42 Preparation of Compound 832-(4-chlorophenoxy)-N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide

¹H NMR (400 MHz, CDCl₃) δ 1.76 (br, 4H), 2.63 (br, 4H), 2.78 (dd, 1H),2.89 (dd, 1H), 4.24 (s, 4H), 4.27 (br, 1H), 4.36 (q, 2H), 4.94 (d, 1H),6.71 (d, 1H), 6.77-6.82 (m, 4H), 6.86 (d, 1H), 7.24 (s, 1H); MS forC₂₃H₂₇ClN₂O₅: [M−H]⁻ 447.

Example 2E43 Preparation of Compound 872-(3,4-dichlorophenoxy)-N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide

¹H NMR (400 MHz, CDCl₃) δ 1.78 (br, 4H), 2.67 (br, 4H), 2.79 (dd, 1H),2.92 (dd, 1H), 4.25 (br, s, 5H), 4.35 (q, 2H), 4.95 (d, 1H), 6.71-6.84(m, 5H), 7.01 (d, 1H), 7.34 (d, 1H); MS for C₂₃H₂₆Cl₂N₂O₅: [M−H]⁻ 482.

Example 2E44 Preparation of Compound 86N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(3-phenoxyphenyl)acetamide

¹H NMR (400 MHz, CDCl₃) δ 1.72 (br, 4H), 2.57 (br, 4H), 2.75-2.80 (m,2H), 3.45 (s, 2H), 4.11-4.13 (m, 1H), 4.23 (s, 4H), 4.84 (d, 1H), 5.86(d, 1H), 6.55 (dd, 1H), 6.71 (d, 1H), 6.74 (d, 1H), 6.80 (br, 1H), 6.85(dd, 1H), 6.92 (dd, 1H), 6.98 (d, 1H), 7.14 (t, 1H), 7.28-7.36 (m, 2H);MS for C₂₉H₃₂N₂O₅: [M−H]⁻ 489.

Example 2E45 Preparation of Compound 2802-(3,4-difluorophenyl)-N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide

¹H NMR (400 MHz, CDCl₃) δ 1.80 (br, 4H, 2.68 (br, 4H), 2.84 (d, 2H),3.45 (s, 2H), 4.17 (m, 1H), 4.25 (s, 4H), 4.88 (d, 1H), 5.88 (d, 1H),6.65 (d, 1H), 6.79 (d, 1H), 6.95 (m, 1H), 6.95 (t, 1H), 7.13 (q, 1H); MSfor C₂₃H₂₆F₂N₂O₄: [M−H]⁻ 434.

Example 2E46 Preparation of Compound 103N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4-(trifluoromethoxy)phenyl)acetamide

¹H NMR (400 MHz, CDCl₃) δ 1.65 (br, 4H), 2.48 (br, 4H), 2.69 (d, 2H),3.40 (s, 2H), 4.08 (m, 1H), 4.17 (s, 4H), 4.80 (s, 1H), 5.84 (t, 1H),6.55 (d, 1H), 6.66 (s, 1H), 6.70 (d, 1H), 7.10 (t, 3H); MS forC₂₄H₂₇F₃N₂O₅: [M−H]⁻ 481.

Example 2E47 Preparation of Compound 90N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-5-(thiophen-2-yl)isoxazole-3-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 1.82 (br, 4H), 2.73-2.81 (m, 4H), 2.89-2.93(m, 1H), 3.02-3.07 (m, 1H), 4.23 (s, 4H), 4.41 (br, 1H), 5.07 (s, 1H),5.30 (d, 1H), 6.74 (s, 1H), 6.83 (t, 2H), 6.90 (s, 1H), 7.12-7.14 (m,2H), 7.47 (d, 1H), 7.52 (d, 1H); MS for C₂₃H₂₅N₃O₅S: [M−H]⁻ 456.

Example 2E48 Preparation of Compound 923-(3-chloro-4-methoxyphenyl)-N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)propanamide

¹H NMR (400 MHz, CDCl₃) δ 1.77 (br, 4H), 2.38 (t, 2H), 2.60 (br, 4H),2.8 (m, 4H), 3.86 (s, 3H), 4.20 (br, 1H), 4.24 (s, 4H), 4.87 (s, 1H),5.80 (d, 1H), 6.66 (d, 1H), 6.8 (m, 3H), 7.00 (d, 1H), 7.18 (s, 1H); MSfor C₂₅H₃₁ClN₂O₅: [M−H]⁻ 475.

Example 2E49 Preparation of Compound 96N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(4-(trifluoromethyl)phenyl)propanamide

¹H NMR (400 MHz, CDCl₃) δ 1.73 (br, 4H), 2.4 (m, 2H), 2.53 (m, 4H), 2.7(m, 2H), 2.90-2.97 (m, 2H), 4.17 (br, 1H), 4.23 (s, 4H), 4.89 (s, 1H),5.83 (br, 1H), 6.68 (d, 1H), 6.79 (d, 2H), 7.24 (d, 2H), 7.50 (d, 2H);MS for C₂₅H₂₉F₃N₂O₅: [M−H]⁻ 479.

Example 2E50 Preparation of Compound 1014-(benzo[d]thiazol-2-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)butanamide

¹H NMR (400 MHz, CDCl₃) δ 1.77 (br, 4H), 2.10-2.15 (m, 2H), 2.24-2.27(m, 2H), 2.64-2.67 (m, 4H), 2.79-2.83 (m, 2H), 3.02 (t, 2H), 4.18 (s,4H), 4.26 (br, 1H), 4.92 (d, 1H), 6.12 (br, 1H), 6.75-6.81 (m, 2H), 6.86(s, 1H), 7.37 (t, 1H), 7.45 (t, 1H), 7.85 (d, 1H), 7.92 (d, 1H); MS forC₂₆H₃₁N₃O₄S: [M−H]⁻ 482.

Example 2E51 Preparation of Compound 102N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-6-(2,3-dihydrobenzo[β][1,4]dioxine-6-sulfonamido)hexanamide

¹H NMR (400 MHz, CDCl₃) δ 1.15-1.20 (m, 2H), 1.38-1.50 (m, 4H), 1.77(br, 4H), 2.08 (q, 2H), 2.63-2.66 (m, 4H), 2.79 (d, 2H), 2.87 (t, 2H),4.2 (m, 9H), 4.91 (br, 1H), 5.93 (br, 1H), 6.77 (q, 2H), 6.84 (s, 1H),6.93 (d, 1H), 7.31 (d, 1H), 7.37 (s, 1H); MS for C₂₉H₃₉N₃O₈S: [M−H]⁻590.

Example 2E52 Preparation of Compound 104N-(5-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-ylamino)-5-oxopentyl)benzamide

¹H NMR (400 MHz, CDCl₃) δ 1.47-1.52 (m, 2H), 1.59-1.69 (m, 2H), 1.77(br, 4H), 2.15-2.21 (m, 2H), 2.62-2.65 (m, 4H), 2.81 (br, 2H), 3.30-3.42(m, 2H), 4.19-4.23 (m, 5H), 4.94 (br, 1H), 5.98 (br, 1H), 6.76 (br, 1H),6.78-6.86 (m, 3H), 7.40-7.50 (m, 3H), 7.80 (d, 2H); MS for C₂₇H₃₅N₃O₅:[M−H]⁻ 482.

Example 2E53 Preparation of Compound 281N1-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-N5-(thiazol-2-yl)glutaramide

¹H NMR (400 MHz, CDCl₃) δ 1.74 (br, 4H), 1.97-2.03 (m, 2H), 2.20-2.26(m, 2H), 2.40-2.45 (m, 2H), 2.64-2.68 (m, 5H), 2.88 (m, 1H), 4.20 (s,4H), 4.26-4.29 (m, 1H), 4.83 (d, 1H), 6.12 (br, 1H), 6.74-6.79 (m, 2H),6.85 (s, 1H), 6.95 (d, 1H), 7.41 (d, 1H); MS for C₂₃H₃₀N₄O₅S: [M−H]⁻475.

Example 2E54 Preparation of Compound 282N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-5-(3,4-dimethoxyphenyl)-5-oxopentanamide

¹H NMR (400 MHz, CDCl₃) δ 1.76 (br, 4H), 1.92-2.00 (m, 2H), 2.21-2.26(m, 2H), 2.60-2.65 (m, 4H), 2.70-2.95 (m, 4H), 3.93 (d, 6H), 4.17-4.23(m, 5H), 4.90 (d, 1H), 5.96 (br, 1H), 6.75-6.79 (m, 2H), 6.85 (s, 1H),6.87 (d, 1H), 7.50 (s, 1H), 7.55 (d, 1H); MS for C₂₈H₃₆N₂O₇: [M−H]⁻ 513.

Example 2E55 Preparation of Compound 283N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-5-oxo-5-p-tolylpentanamide

¹H NMR (400 MHz, CDCl₃) δ 1.77 (br, 4H), 1.96-2.02 (m, 2H), 2.21-2.26(m, 2H), 2.40 (s, 3H), 2.63-2.80 (m, 4H), 2.82-2.95 (m, 4H), 4.18-4.23(m, 5H), 4.91 (d, 1H), 5.94 (br, 1H), 6.74-6.77 (m, 2H), 6.85 (s, 1H),7.26 (d, 2H), 7.81 (d, 2H); MS for C₂₇H₃₄N₂O₅: [M−H]⁻ 467.

Example 2E56 Preparation of Compound 113N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-pyrrolidin-1-yl)propan-2-yl)-5-oxo-5-phenylpentanamide

¹H NMR (400 MHz, CDCl₃) δ 1.76 (br, 4H), 1.95-2.01 (m, 2H), 2.22-2.25(m, 2H), 2.62-2.63 (m, 4H), 2.78-2.95 (m, 4H), 4.17-4.22 (m, 5H), 4.91(sd, 1H), 5.99 (br, 1H), 6.77 (st, 2H), 6.85 (s, 1H), 7.44-7.58 (m, 3H),7.92 (d, 2H); MS for C₂₆H₃₂N₂O₅: [M−H]⁻ 453.

Example 2E57 Preparation of Compound 284N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-5-(4-isopropoxyphenyl)-5-oxopentanamide

¹H NMR (400 MHz, CDCl₃) δ 1.36 (d, 6H), 1.75 (br, 4H), 1.90-2.02 (m,2H), 2.20-2.25 (m, 2H), 2.60-2.66 (m, 4H), 2.70-2.86 (m, 4H), 4.17 (s,4H), 4.22 (br, 1H), 4.62-4.65 (m, 1H), 4.89 (sd, 1H), 6.07 (d, 1H), 6.77(s, 2H), 6.85 (s, 1H), 6.87 (d, 2H), 7.86 (d, 2H); MS for C₂₉H₃₈N₂O₆:[M−H]⁻ 511.

Example 2E58 Preparation of Compound 140N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-6-(4-methoxy-3,5-dimethylphenyl)-6-oxohexanamide

¹H NMR (400 MHz, CDCl₃) δ 1.61-1.63 (m, 4H), 1.77 (br, 4H), 2.16 (t,2H), 2.32 (s, 6H), 2.61-2.67 (m, 4H), 2.74-2.89 (m, 2H), 2.91 (t, 2H),3.75 (s, 3H), 4.21 (br, 5H), 4.90 (sd, 1H), 5.93 (br, 1H), 6.75-6.82 (m,2H), 6.85 (sd, 1H), 7.61 (s, 2H); MS for C₃₀H₄₀N₂O₆: [M−H]⁻ 525.

Example 2E59 Preparation of Compound 141N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-6-(4-methoxyphenyl)-6-oxohexanamide

¹H NMR (400 MHz, CDCl₃) δ 1.62-1.64 (m, 4H), 1.76 (br, 4H), 2.17 (t,2H), 2.61-2.65 (m, 4H), 2.72-2.79 (m, 2H), 2.89 (t, 2H), 3.86 (s, 3H),4.20 (br, 5H), 4.89 (d, 1H), 6.01 (br, 1H), 6.77 (q, 2H), 6.85 (s, 1H),6.91 (d, 2H), 7.90 (d, 2H); MS for C₂₈H₃₆N₂O₆: [M−H]⁻ 497.

Example 2E60 Preparation of Compound 1556-(4-tert-butylphenyl)-N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-6-oxohexanamide

¹H NMR (400 MHz, CDCl₃) δ 1.34 (s, 9H), 1.63-1.65 (m, 4H), 1.77 (br,2.17 (t, 2H), 2.64-2.66 (br, 4H), 2.75 (dd, 1H), 2.2.81 (dd, 1H), 2.91(t, 2H), 4.20 (br, 5H), 4.90 (d, 1H), 6.02 (br, 1H), 6.77-6.82 (q, 2H),6.85 (d, 1H), 7.46 (d, 2H), 7.86 (d, 2H); MS for C₃₁H₄₂N₂O₅: [M−H]⁻ 523.

Example 2E61 Preparation of Compound 156N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-7-(4-methoxyphenyl)-7-oxoheptanamide

¹H NMR (400 MHz, CDCl₃) δ 1.25-1.30 (m, 2H), 1.55-1.70 (m, 4H), 1.77(br, 4H), 2.13 (t, 2H), 2.61-2.66 (m, 4H), 2.74-2.82 (m, 2H), 2.88 (t,2H), 3.86 (s, 3H), 4.20 (br, 5H), 4.90 (d, 1H), 5.93 (br, 1H), 6.78 (q,2H), 6.85 (s, 1H), 6.91 (d, 2H), 7.92 (d, 2H); MS for C₂₉H₃₈N₂O₆: [M−H]⁻511.

Example 2E62 Preparation of Compound 144N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-8-(4-methoxyphenyl)-8-oxooctanamide

¹H NMR (400 MHz, CDCl₃) δ 1.25-1.33 (m, 4H), 1.54 (m, 2H), 1.68 (t, 2H),1.78 (br, 4H), 2.11 (br, 2H), 2.65 (br, 4H), 2.76-2.11 (m, 4H), 3.86 (s,3H), 4.21 (br, 5H), 4.90 (br, 1H), 6.02 (d, 1H), 6.78-6.84 (m, 3H), 6.91(d, 2H), 7.92 (d, 2H); MS for C₃₀H₄₀N₂O₆: [M−H]⁻ 525.

Example 2E63 Preparation of Compound 1597-(4-chlorophenyl)-N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-7-oxoheptanamide

¹H NMR (400 MHz, CDCl₃) δ 1.26-1.37 (m, 2H), 1.57 (m, 2H), 1.68 (m, 2H),1.77 (br, 4H), 2.13 (t, 2H), 2.62-2.65 (m, 4H), 2.76-2.82 (m, 2H), 2.90(t, 2H), 4.20 (br, 5H), 4.90 (d, 1H), 5.93 (d, 1H), 6.78 (q, 2H), 6.85(s, 1H), 7.42 (d, 2H), 7.87 (d, 2H); MS for C₂₈H₃₅ClN₂O₅: [M−H]⁻ 515.

Example 2E64 Preparation of Compound 1607-(4-tert-butylphenyl)-N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-7-oxoheptanamide

¹H NMR (400 MHz, CDCl₃) δ 1.27-1.34 (m, 11H), 1.56-1.71 (m, 4H), 1.77(br, 4H), 2.13 (t, 2H), 2.63-2.66 (m, 4H), 2.76-2.819 (m, 2H), 2.91 (t,2H), 4.20 (br, 5H), 4.90 (sd, 1H), 5.90 (d, 1H), 6.81 (q, 2H), 6.85 (s,1H), 7.46 (d, 2H), 7.88 (d, 2H); MS for C₃₂H₄₄N₂O₅: [M−H]⁻ 537.

Example 2E65 Preparation of Compound 168N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-7-(4-methoxyphenyl)-7-oxoheptanamide(2S,3S)-2,3-dihydroxysuccinate

¹H NMR (400 MHz, CD₃OD) δ 1.15-1.19 (m, 2H), 1.40-1.47 (m, 2H), 1.60 (m,2H), 2.02 (br, 4H), 2.09-2.21 (m, 2H), 2.90 (t, 2H), 3.35-3.49 (m, 5H),3.83 (s, 3H), 4.12 (br, 4H), 4.38 (s, 2H), 4.43 (m, 1H), 4.74 (sd, 1H),6.71 (d, 1H), 6.79 (dq, 1H), 6.86 (sd, 1H), 6.96 (d, 2H), 7.92 (d, 2H);MS for C₂₉H₃₈N₂O₆.C₄H₆O₆: [M−H]⁻ 661.

Example 2E66 Preparation of Compound 162N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-4-(4-isopropoxyphenyl)-4-oxobutanamide

¹H NMR (400 MHz, CDCl₃) δ 1.35 (d, 6H), 1.77 (br, 4H), 2.52-2.56 (m,2H), 2.64-2.83 (m, 6H), 3.09-3.36 (m, 2H), 4.22 (br, 5H), 4.63-4.66 (m,1H), 4.89 (sd, 1H), 6.13 (d, 1H), 6.78 (s, 2H), 6.88 (t, 3H), 7.90 (d,2H); MS for C₂₈H₃₆N₂O₆: [M−H]⁻ 497.

Example 2E67 Preparation of Compound 176N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-4-oxo-4-(4-(trifluoromethyl)phenyl)butanamide(2S,3S)-2,3-dihydroxysuccinate

¹H NMR (400 MHz, CD₃OD) δ 2.08 (br, 4H), 2.54-2.72 (m, 2H), 3.24-3.48(m, 6H), 4.19 (s, 4H), 4.29 (m, 4H), 4.74 (sd, 1H), 6.76 (d, 1H), 6.86(d, 1H), 6.92 (s, 1H), 7.81 (d, 2H), 8.13 (d, 2H); MS forC₂₆H₂₉F₃N₂O₅.C₄H₆O₆: [M−H]⁻ 657.

Example 2E68 Preparation of Compound 65 (Genz-528152-1)2-(3′-chlorobiphenyl-4-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide

¹H NMR (400 MHz, CDCl₃) δ 1.70 (br, 4H), 2.54 (br, 4H), 2.72-2.81 (m,2H), 3.53 (s, 2H), 4.12-4.23 (m, 5H), 4.85 (d, 1H), 5.82 (d, 1H), 6.58(dd, 1H), 6.70 (sd, 1H), 6.73 (d, 1H), 7.19 (d, 1H), 7.32-7.34 (m, 1H),7.38 (t, 1H), 7.46-7.49 (m, 1H), 7.52 (d, 2H), 7.59 (d, 1H);C₂₉H₃₁ClN₂O₄: [M−H]⁻ 507.

Example 2E69 Preparation of Compound 262N-[2-Hydroxy-2-(4-methoxy-phenyl)-1-pyrrolidin-1-ylmethyl-ethyl]-3-(4-methoxy-phenoxy)-propionamide

¹H NMR (CDCl₃ 400 mHz, ppm); 1.75 (m, 4H), 2.55 (m, 2H), 2.65 (m, 4H),2.85 (m, 2H), 3.8 (s, 6H), 4.1 (m, 2H), 4.25 (m, 1H), 5.0 (d, 1H), 6.5(br. d, 1H), 6.8 (m, 4H), 7.25 (m, 4H). M/Z for C₂₄H₃₂N₂O₅ [M−H]⁺ 429.

Example 2E70 Preparation of Compound 2705-(4-Isopropoxy-phenyl)-5-oxo-pentanoic acid[2-hydroxy-2-(4-methoxy-phenyl)-1-pyrrolidin-1-ylmethyl-ethyl]amide

¹H NMR (CDCl₃ 400 mHz, ppm); 1.4 (d, 6H), 1.8 (m, 4H), 2.0 (m, 2H), 2.2(m, 2H), 2.6 (m, 4H), 2.8 (m, 4H), 3.75 (s, 3H), 4.25 (m, 1H), 4.65 (m,1H), 5.0 (d, 1H), 5.95 (br. d, 1H), 6.85 (m, 4H), 7.25 (m, 2H), 7.9 (m,2H). M/Z for C₂₄H₃₂N₂O₅ [M−H]⁺ 483.3.

Example 2E71 Preparation of Compound 2857-(4-Methoxy-phenyl)-7-oxo-heptanoic acid[2-hydroxy-2-(4-methoxy-phenyl)-1-pyrrolidin-1-ylmethyl-ethyl]-amide

¹H NMR (CDCl₃ 400 mHz, ppm); 1.25 (m, 2H), 1.6 (m, 4H), 1.8 (m, 4H),2.15 (m, 2H), 2.65 (m, 4H), 2.85 (m, 4H), 3.75 (s, 3H), 3.9 (s, 3H), 4.2(m, 1H), 5.0 (d, 1H), 5.9 (br. d, 1H), 6.85 (d, 2H), 6.95 (d, 2H), 7.2(d, 2H), 7.95 (d, 2H). M/Z for C₂₄H₃₂N₂O₅ [M−H]⁺ 483.3

Example 2E72 Preparation of Compound 262N-[2-Hydroxy-2-(4-methoxy-phenyl)-1-pyrrolidin-1-ylmethyl-ethyl]-3-(4-methoxy-phenoxy)-propionamide

¹H NMR (CDCl₃ 400 mHz, ppm); 1.75 (m, 4H), 2.55 (m, 2H), 2.65 (m, 4H),2.85 (m, 2H), 3.8 (s, 6H), 4.1 (m, 2H), 4.25 (m, 1H), 5.0 (d, 1H), 6.5(br. d, 1H), 6.8 (m, 4H), 7.25 (m, 4H). M/Z for C₂₄H₃₂N₂O₅ [M−H]⁺ 429.

Example 2E73 Preparation of Compound 2705-(4-Isopropoxy-phenyl)-5-oxo-pentanoic acid[2-hydroxy-2-(4-methoxy-phenyl)-1-pyrrolidin-1-lymethyl-ethyl]amide

¹H NMR (CDCl₃ 400 mHz, ppm); 1.4 (d, 6H), 1.8 (m, 4H), 2.0 (m, 2H), 2.2(m, 2H), 2.6 (m, 4H), 2.8 (m, 4H), 3.75 (s, 3H), 4.25 (m, 1H), 4.65 (m,1H), 5.0 (d, 1H), 5.95 (br. d, 1H), 6.85 (m, 4H), 7.25 (m, 2H), 7.9 (m,2H). M/Z for C₂₄H₃₂N₂O₅ [M−H]⁺ 483.3.

Example 2E74 Preparation of Compound 305

¹H NMR (CDCl₃ 400 mHz, ppm); 1.25 (m, 14H), 1.6 (m, 4H), 1.8 (m, 4H),2.1 (t, 2H), 2.6 (t, 2H), 2.8 (m, 6H), 4.2 (m, 5H), 4.9 (d, 1H), 6.0 (brd, 1H), 6.8 (m, 3H), 7.2 (m, 1H), 7.5 (m, 1H), 8.4 (m, 2H). M/Z forC₂₄H₃₂N₂O₅ [M−H]⁺ 538.

Example 2E75 Preparation of Compound 320 Octanoic acid[2-hydroxy-2(4-methoxy-phenyl)-1-Pyrrolidin1-ylmethyl-ethyl]-amide

¹H NMR (CDCl₃ 400 mHz, ppm); 0.9 (t, 3H), 1.2 (m, 8H), 1.5 (m, 2H), 1.8(m, 4H), 2.1 (t, 2H), 2.65 (m, 4H), 2.8 (d, 2H), 3.8 (s, 3H), 4.2 (m,1H), 4.95 (d, 1H), 5.9 (br d, 1H), 6.9 (2s, 2H), 7.25 (m, 2H). M/Z forC₂₂H₃₆N₂O₃ [M−H]⁺ 377.4.

Example 2E76 Preparation of Cyclic Amide Analogs

Cyclic amide analogs were prepared according to Scheme 6.2-Amino-1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3-pyrrolidin-1-yl-propan-1-olwas prepared according to the preparation of intermediate 4 of U.S. Pat.No. 6,855,830 B2. This amine was coupled with various nitriles inpotassium carbonate and glycerol, under an atmosphere of nitrogen, forexample, at 115° C. for 18 hours. Compound 323 characterized by thefollowing structural formula was prepared by following Scheme 6.Compound 323 was purified by column chromatography using a mixture ofmethanol and methylene chloride.

¹H NMR (CDCl₃ 400 mHz, ppm); 0.95 (t, 3H), 1.35 (m, 2H), 1.6 (m, 2H),1.8 (m, 4H), 2.7 (m, 6H), 2.8 (m, 2H), 4.2 (m, 5H), 5.4 (d, 1H), 6.85(m, 3H), 7.2 (m, 2H), 7.9 (d, 2H). M/Z for C₂₄H₃₂N₂O₅ [M−H]⁺ 421.54.

Example 2E77 Preparation ofN-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-5-(4-(2-methoxyethoxy)phenyl)-5-oxopentanamide

¹H NMR (CDCl₃, 400 mHz, ppm): 1.25 (t, 3H), 1.8 (br, 4H), 1.95 (m, 2H),2.05 (t, 3H), 2.25 (m, 2H), 3.65 (m, 4H), 2.90 (m, 4H), 3.4 (s, 4H), 3.8(m, 2H), 4.15 (m, 9H), 4.95 (br, 1H), 5.95 (br, 1H), 6.88-6.95 (m, 5H),7.9 (m, 2H). M/Z for C₂₉H₃₈N₂O₇ [M+H]=527.

Example 2E78 Preparation ofN-((1R,2R)-1-(4-chlorophenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(4-methoxyphenoxy)propanamide

¹H NMR (CDCl₃, 400 mHz, ppm): 1.76 (br, 4H), 2.52-2.57 (sq, 2H),2.60-2.73 (br, 4H), 2.88-2.96 (st, 2H), 3.8 (s, 3H), 3.96-4.0 (m, 1H),4.06-4.11 (1H), 4.21-4.24 (m, 1H), 5.07 (d, 1H), 6.57 (bd, 1H),6.77-6.87 (sq, 4H), 7.20-7.27 (sd, 6H). M/Z for C₂₃H₂₉ClN₂O₄ [M+H]=433.

Example 2E79 Preparation ofN-((1R,2R)-1-(4-chlorophenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-6-(4-methoxyphenyl)-6-oxohexanamide

¹H NMR (CDCl₃, 400 mHz, ppm): 1.54-1.62 (br, 4H), 1.79 (br, 4H), 2.14(t, 2H), 2.63-2.69 (br, 4H), 2.83-2.89 (m, 4H), 3.88 (s, 3H), 4.24 (br,1H), 5.03 (d, 1H), 5.93 (d, 1H), 6.93 (d, 2H), 7.26-7.32 (m, 4H), 7.93(d, 2H). M/Z for C₂₆H₃₃ClN₂O₄ [M+H]=473.

Example 2E80 Preparation ofN-((1R,2R)-1-hydroxy-1-(4-methoxy-3-methylphenyl)-3-(pyrrolidin-1-yl)propan-2-yl)-6-(4-methoxyphenyl)-6-oxohexanamide

¹H NMR (CDCl₃, 400 mHz, ppm): 1.77 (br, 4H), 1.91-2.0 (m, 2H), 2.18 (s,3H), 2.2-2.25 (m, 2H), 2.62-2.69 (m, 4H), 2.77-2.89 (m, 4H), 3.75 (s,3H), 3.88 (s, 3H), 4.23 (m, 1H), 4.96 (sd, 1H), 5.93 (br, 1H), 6.75 (br,1H), 6.94 (d, 2H), 7.1 (br, 2H), 7.88 (m, 2H). M/Z for C₂₈H₃₈N₂O₅[M+H]=483.

Example 2E81 Preparation ofN-((1R,2R)-1-hydroxy-1-(4-methoxy-3-methylphenyl)-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4-(trifluoromethoxy)phenyl)acetamide

¹H NMR (CDCl₃, 400 mHz, ppm): 1.73 (br, 4H), 2.20 (s, 3H), 2.55 (br,4H), 2.81 (st, 2H), 3.46 (s, 2H), 3.82 (s, 3H), 4.15 (m, 1H), 4.92 (sd,1H), 5.85 (br, 1H), 672 (d, 1H), 6.95 (sd, 1H), 7.00 (br, 1H), 7.2 (m,4H). M/Z for C₂₄H₂₉F₃N₂O₄ [M+H]=467.

Example 2E82 Preparation ofN-((1R,2R)-1-hydroxy-3-(pyrrolidin-1-yl)-1-(2,2,3,3-tetrafluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)propan-2-yl)octanamide

¹H NMR (CDCl₃, 400 mHz, ppm): 0.9 (t, 3H), 1.2 (m, 11H), 1.5 (bm, 8H),1.8 (br, 4H), 2.1 (m, 2H), 2.65 (m, 4H), 2.90 (m, 2H), 4.2 (m, 1H), 5.05(d, 1H), 5.85 (br, 1H), 7.2 (m, 3H). M/Z for C₂₃H₃₂F₄N₂O₄ [M+H]=477.

Example 2E83 Preparation ofN-((1R,2R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4-(trifluoromethoxy)phenyl)acetamide

¹H NMR (CDCl₃, 400 mHz, ppm): 1.75 (br, 4H), 2.55 (br, 4H), 2.85 (m,2H), 3.45 (s, 2H), 4.1 (m, 1H), 5.0 (d, 1H), 5.85 (br, 1H), 6.8-6.95(3H), 7.1-7.20 (4H). M/Z for C₂₃H₂₃F₅N₂O₅ [M+H]=503.

Example 2E84 Preparation ofN-((1R,2R)-1-hydroxy-1-(4-(2-phenoxyethoxy)phenyl)-3-(pyrrolidin-1-yl)propan-2-yl)-6-(4-methoxyphenyl)-6-oxohexanamide

¹H NMR (CDCl₃, 400 mHz, ppm): 1.6 (m, 4H), 1.8 (m, 4H), 2.15 (t, 2H),2.7 (m, 4H), 2.85 (m, 4H), 3.8 (s, 3H), 4.25 (m, 1H), 4.3 (s, 3H), 5.0(d, 1H), 5.95 (br, 1H), 6.9 (m, 7H), 7.2 (m, 4H), 7.95 (m, 2H). M/Z forC₃₄H₄₂N₂O₆ [M+H]=575.

Example 2E85 Preparation ofN-((1R,2R)-1-(4-(cyclobutylmethoxy)phenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-6-(4-methoxyphenyl)-6-oxohexanamide

¹H NMR (CDCl₃, 400 mHz, ppm): 1.6 (br, 4H), 1.9 (m, 9H), 2.05 (m, 5H),2.75-3.0 (m, 9H), 3.8 (m, 5H), 4.3 (m, 1H), 5.0 (m, 1H), 6.2 (br, 1H),6.9 (m, 4H), 7.25 (m, 2H), 7.9 (m, 2H). M/Z for C₃₁H₄₂N₂O₅ [M+H]=523.

Example 2E86 Preparation ofN-((1R,2R)-1-(4-(4-fluorobutoxy)phenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-6-(4-methoxyphenyl)-6-oxohexanamide

¹H NMR (CDCl₃, 400 mHz, ppm): 1.6 (m, 8H), 1.8 (m, 10H), 2.15 (t, 2H),2.65 (m, 4H), 2.8 (d, 2H), 2.9 (m, 5H), 2.95 (s, 3H), 4.0 (t, 2H), 4.15(m, 1H), 4.45 (t, 1H), 4.55 (t, 1H), 4.95 (br, 2H), 5.9 (br, 1H), 6.90(m, 4H), 7.20 (m, 2H), 7.95 (m, 2H), 8.05 (br, 1H). M/Z for C₃₀H₄₁FN₂O₅[M+H]=529.

Example 2E87 Preparation ofN-((1R,2R)-1-hydroxy-3-(pyrrolidin-1-yl)-1-(4-(3-(p-tolyloxy)propoxy)phenyl)propan-2-yl)-6-(4-methoxyphenyl)-6-oxohexanamide

¹H NMR (CDCl₃, 400 mHz, ppm): 1.65 (m, 4H), 1.8 (m, 4H), 2.15 (t, 2H),2.25 (t, 2H), 2.3 (s, 3H), 2.65 (m, 4H), 2.8 (m, 2H), 2.9 (t, 2H), 3.85(s, 3H), 4.15 (m, 4H), 4.25 (m, 1H), 4.95 (br, 1H), 6.85 (br, 1H),6.8-6.95 (m, 6H), 7.05 (m, 2H), 7.2 (m, 2H), 7.95 (2H). M/Z forC₃₆H₄₆N₂O₆ [M+H]=603.

Example 2E88 Preparation ofN-((1R,2R)-1-(4-butoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-6-(4-methoxyphenyl)-6-oxohexanamide

¹H NMR (CDCl₃, 400 mHz, ppm): 1.0 (t, 3H), 1.5 (m, 2H), 1.65 (m, 4H),1.8 (m, 6H), 2.15 (t, 2H), 2.65 (m, 4H), 2.8 (m, 2H), 2.9 (t, 2H), 3.85(s, 3H), 3.9 (t, 2H), 4.15 (m, 1H), 4.95 (br, 1H), 5.90 (br, 1H),6.8-6.95 (m, 4H), 7.2 (br, 2H), 7.90 (br, 2H). M/Z for C₃₀H₄₂N₂O₅[M+H]=511.

Example 2E89 Preparation ofN-((1R,2R)-1-(4-(hexyloxy)phenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-5-(4-(2-methoxyethoxy)phenyl)-5-oxopentanamide

¹H NMR (CDCl₃, 400 mHz, ppm): 0.95 (t, 3H), 1.35 (m, 4H), 1.45 (m, 2H),1.7 (m, 6H), 1.95 (m, 2H), 2.20 (m, 2H), 2.65 (m, 4H), 2.85 (m, 4H),3.45 (s, 3H), 3.75 (m, 2H), 3.90 (t, 2H), 4.15 (m, 2H), 4.25 (m, 1H),4.95 (m, 1H), 6.0 (br, 1H), 6.8 (m, 2H), 6.9 (m, 2H), 7.2 (m, 2H), 7.90(m, 2H). M/Z for C₃₃H₄₈N₂O₆ [M+H]=569.

Example 2E90 Preparation ofN-((1R,2R)-1-(4-(hexyloxy)phenyl)-1-hydroxy-3-((S)-3-hydroxypyrrolidin-1-yl)propan-2-yl)-3-(4-methoxyphenoxy)propanamide

¹H NMR (CDCl₃, 400 mHz, ppm): 0.95 (t, 3H), 1.35 (m, 4H), 1.45 (m, 2H),1.75 (m, 3H), 2.1 (m, 1H), 2.4 (m, 1H), 2.55 (t, 2H), 2.75 (m, 3H), 2.85(m, 1H), 3.0 (m, 1H), 3.75 (s, 3H), 3.90 (t, 2H), 4.05 (m, 2H), 4.1 (m,1H), 4.15 (m, 1H), 5.0 (br, 1H), 6.6 (br, 1H), 6.8 (m, 6H), 7.2 (m, 2H).M/Z for C₂₉H₄₂N₂O₆ [M+H]=515.

Example 2E91 Preparation of2-(4′-chlorobiphenyl-4-yl)-N-((1R,2R)-3-((R)-3-fluoropyrrolidin-1-yl)-1-hydroxy-1-(4-isopropoxyphenyl)propan-2-yl)acetamide

¹H NMR (CDCl₃, 400 mHz, ppm): 1.15 (m, 6H), 2.10 (m, 2H), 2.4 (q, 1H),2.5-2.75 (m, 4H), 2.95 (m, 2H), 3.55 (d, 2H), 4.15 (m, 1H), 4.45 (m,1H), 4.85 (br, 1H), 5.10 (m, 1H), 5.9 (br, 1H), 6.75 (m, 2H), 7.05 (br,2H), 7.20 (m, 2H), 7.4 (m, 2H), 7.5 (m, 4H). M/Z for C₃₀H₃₄ClFN₂O₃[M+H]=528.

Example 2E92 Preparation ofN-((1R,2R)-1-hydroxy-3-((S)-3-hydroxypyrrolidin-1-yl)-1-(4-isopropoxyphenyl)propan-2-yl)-3-(4-methoxyphenoxy)propanamide

¹H NMR (CDCl₃, 400 mHz, ppm): 1.35 (d, 6H), 1.7 (m, 1H), 2.1 (m, 1H),2.45 (m, 1H), 2.55 (t, 2H), 2.7-2.9 (m, 4H), 3.0 (m, 1H), 3.8 (s, 3H),4.05 (m, 1H), 4.15 (m, 1H), 4.20 (m, 1H), 4.35 (m, 1H), 4.5 (m, 1H),4.95 (d, 1H), 6.55 (br, 1H), 6.75-6.85 (m, 6H), 7.2 (m, 2H). M/Z forC₂₆H₃₆N₂O₆ [M+H]=473.

Example 2E93 Preparation ofN-((1R,2R)-1-(4-(4-fluorobutoxy)phenyl)-1-hydroxy-3-((R)-3-hydroxypyrrolidin-1-yl)propan-2-yl)-5-(4-methoxyphenyl)-5-oxopentanamide

¹H NMR (400 MHz, CDCl₃) δ=1.7-2.2 (m, 12H), 2.4 (dd, 1H), 2.65-2.9 (m,6H), 3.0 (dd, 1H), 3.90 (s, 3H), 3.91 (dd, 2H), 4.1-4.22 (m, 1H),4.3-4.4 (m, 1H), 4.4 (dd, 1H), 4.6 (dd, 1H), 4.91 (d, 1H), 6.19 (d, 1H),6.83 (d, 2H), 6.92 (d, 2H), 7.22 (d, 2H), 7.9 (d, 2H); MS forC₂₉H₃₉FN₂O₆ m/z 531 [M+H].

Example 2E94 Preparation ofN-((1R,2R)-1-(4-(4-fluorobutoxy)phenyl)-1-hydroxy-3-((R)-3-hydroxypyrrolidin-1-yl)propan-2-yl)-8-methoxyoctanamide

¹H NMR (400 MHz, CDCl₃) δ=1.2-1.34 (m, 6H), 1.45-1.6 (m, 4H), 1.7-1.8(m, 1H), 1.86-1.95 (m, 4H), 2.0-2.2 (m, 4), 2.4-2.5 (m, 2H), 2.7-2.8 (m,4H), 2.98 (dd, 1H), 3.3 (s, 3H), 3.53 (dd, 1H), 4.0 (dd, 2H), 4.1-4.2(m, 1H), 4.3-4.4 (m, 1H), 4.5 (dd, 1H), 4.58 (dd, 1H), 4.9 (d, 1H), 5.9(d, 1H), 6.85 (d, 2H), 7.22 (d, 2H); MS for C₂₆H₄₃FN₂O₅ m/z 483 [M+H]

Example 2E95 Preparation ofN-((1R,2R)-1-(4-(4-fluorobutoxy)phenyl)-1-hydroxy-3-((R)-3-hydroxypyrrolidin-1-yl)propan-2-yl)-4-(4-methoxyphenoxy)butanamide

¹H NMR (400 MHz, CDCl₃) δ=1.6-2.2 (m, 9H), 2.3-2.5 (m, 4H), 2.6-2.8 (m,5), 2.9 (dd, 1H), 3.7 (s, 3H), 3.85 (dd, 2H), 3.95 (dd, 2H), 4.2-4.3 (m,2H), 4.5 (dd, 1H), 4.6 (dd, 1H), 4.9 (d, 1H), 6.0 (d, 1H), 6.7-7 (m,6H), 7.1-7.2 (d, 2H); MS for C₂₈H₃₉FN₂O₆ m/z 519 [M+H].

Example 2E96 Preparation ofN-((1R,2R)-1-(4-(4-fluorobutoxy)phenyl)-1-hydroxy-3-((R)-3-hydroxypyrrolidin-1-yl)propan-2-yl)-3-(4-methoxyphenoxy)propanamide

¹H NMR (400 MHz, CDCl₃) δ=1.6-1.7 (m, 1H), 1.8-2 (m, 4H), 2.1-2.2 (m,1), 2.4-2.5 (m, 1H), 2.6 (t, 2H), 2.7-2.85 (m, 4H), 3.0 (dd, 1H), 3.7(s, 3H), 4.0 (t, 2H), 4.1-4.3 (m, 4H), 4.5 (dd, 1H), 4.6 (dd, 1H), 4.98(d, 1H), 6.6 (d, 1H), 6.7-6.9 (m, 6H), 7.1-7.22 (d, 2H); MS forC₂₇H₃₇FN₂O₆ m/z 505 [M+H].

Example 2E97 Preparation ofN-((1R,2R)-1-(4-(4-fluorobutoxy)phenyl)-1-hydroxy-3-((R)-3-hydroxypyrrolidin-1-yl)propan-2-yl)-7-(4-methoxyphenyl)-7-oxoheptanamide

¹H NMR (400 MHz, CDCl₃) δ=1.1-1.4 (m, 3H), 1.5-2.0 (m, 12H), 2.1-2.2(dd, 4H), 2.4-2.90 (m, 10H), 3.0 (dd, 1H), 3.75 (s, 3H), 3.9 (dd, 2H),4.1-4.2 (m, 1H), 4.3-4.4.5 (m, 2H), 4.57 (dd, 1H), 4.9 (d, 1H), 5.9 (d,1H), 6.8 (d, 2H), 6.9 (d, 2H), 7.2 (d, 2H), 7.9 (d, 2H); MS forC₃₁H₄₃FN₂O₆ m/z 559 [M+H].

Example 2E98 Preparation ofN-((1R,2R)-1-(4-(4-fluorobutoxy)phenyl)-1-hydroxy-3-((R)-3-hydroxypyrrolidin-1-yl)propan-2-yl)-6-(4-methoxyphenyl)-6-oxohexanamide

¹H NMR (400 MHz, CD₃OD) δ=1.4-1.6 (m, 4H), 1.6-1.8 (m, 5H), 2.0-2.2 (m,1H), 2.2-2.3 (m, 2H), 2.4-2.6 (m, 3H), 2.7-3.0 (m, 5H), 3.8 (s, 3H), 3.9(dd, 1H), 4.1-4.25 (m, 1H), 4.3-4.38 (m, 1H), 4.4 (dd, 1H), 4.5 (dd,1H), 6.8 (d, 2H), 7.1 (d, 2H), 7.2 (d, 2H), 8 (d, 2H); MS forC₃₀R₄₁FN₂O₆ m/z 545 [M+H]

Example 2E99 Preparation ofN-((1S,2R)-1-(5-chlorothiophen-2-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(4-methoxyphenoxy)propanamide

¹H NMR (400 MHz, CDCl₃) δ=1.7 (broad s, 4H), 2.5-2.7 (m, 7H), 2.8 (dd,1H), 2.94 (dd, 1H), 3.77 (s, 3H), 4.1-4.2 (m, 2H), 4.3-4.35 (m, 1H),5.18 (d, 1H), 6.55 (d, 1H), 6.66 (d, 1H), 6.67 (d, 1H), 6.7-6.9 (m, 4H);MS for C₂₁H₂₇ClN₂O₄S m/z 439 [M+H].

Example 2E100 Preparation ofN-((1S,2R)-1-hydroxy-1-(3-methylthiophen-2-yl)-3-(pyrrolidin-1-yl)propan-2-yl)-3-(4-methoxyphenoxy)propanamide2,2,2-trifluoroacetate

¹H NMR (400 MHz, CD₃OD) δ=1.8-2.2 (m, 4H), 2.24 (s, 3H), 2.5-2.8 (m,2H), 3.0-3.2 (m, 2H), 3.5 (dd, 2H), 3.7 (s, 3H), 3.6-3.8 (m, 2H),4.0-4.2 (m, 2H), 4.5 (dd, 1H), 5.2 (s, 1H), 6.8 (d, 1H), 6.84 (broad s,4H), 7.2 (d, 1H); MS for C₂₂H₃₀N₂O₄S m/z 419 [M+H].

Example 2E101 Preparation of Compound 257N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-morpholinopropan-2-yl)-3-(4-methoxyphenoxy)propanamide

¹H NMR (400 MHz, CDCl₃) δ=2.4-2.6 (m, 7H), 2.7 (dd, 1H), 3.5-3.7 (m,4H), 3.8 (s, 3H), 4-4.2 (m, 2H), 4.2 (s, 4H), 4.2-4.3 (m, 1H), 4.9 (d,1H), 6.5 (d, 1H), 6.7-6.9 (m, 7H); MS for C₂₅H₃₂N₂O₇ m/z 473.1 [M+H].

Example 2E102 Preparation of Compound 261N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(piperidin-1-yl)propan-2-yl)-3-(4-methoxyphenoxy)propanamide

¹H NMR (400 MHz, CDCl₃) δ=1.4 (br, 2H), 1.6 (br, 4H), 2.2-2.8 (m, 6H),3.8 (s, 3H), 4.0-4.2 (m, 2H), 4.2 (s, 4H), 4.2-4.3 (m, 1H), 4.9 (s, 1H),6.4 (d, 1H), 6.7-6.9 (m, 7H); MS for C₂₅H₃₄N₂O₆ m/z 471.1 [M+H].

Example 2B1 Preparation of Compound 61-benzyl-3-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)urea

¹H NMR (400 MHz, CDCl₃) δ=1.7 (s, 4H), 2.4-2.6 (m, 5H), 2.6-2.7 (dd,1H), 4.0 (m, 1H), 4.2 (s, 4H), 4.3 (m, 2H), 4.8 (d, 1H), 4.86 (d, 1H),5.0 (br, 1H), 6.6-6.9 (m, 3H), 7.2-7.4 (m, 5H); MS for C₂₃H₂₉N₃O₄ m/z412.2 [M+H].

Example 2B2 Preparation of Compound 171-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(4-fluorobenzyl)urea

¹H NMR (400 MHz, CDCl₃) δ=1.6 (s, 4H), 2.4-2.6 (m, 6H), 3.9 (m, 1H),4.0-4.1 (m, 2H), 4.13 (s, 4H), 4.7 (d, 1H), 5.4 (d, 1H), 6.6-7.1 (m,7H); MS for C₂₃H₂₈FN₃O₄ m/z 430.2 [M+H].

Example 2B3 Preparation of Compound 401-(4-bromobenzyl)-3-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)urea

¹H NMR (400 MHz, CDCl₃) δ=1.7 (s, 4H), 2.4-2.8 (m, 6H), 4.0 (m, 1H),4.1-4.2 (m, 2H), 4.2 (s, 4H), 4.8 (d, 1H), 5.3 (d, 1H), 5.6-5.8 (br,1H), 6.8-7.0 (m, 3H), 7.0 (d, 2H), 7.4 (d, 2H); MS for C₂₃H₂₈BrN₃O₄ m/z490 [M], 491 [M+H], 492 [M+2].

Example 2B4 Preparation of Compound 411-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(4-methoxybenzyl)urea

¹H NMR (400 MHz, CDCl₃) δ=1.6 (s, 4H), 2.4-2.6 (m, 6H), 3.7 (s, 3H), 3.9(m, 1H), 4.1 (d, 2H), 4.2 (s, 4H), 4.7 (d, 1H), 5.2 (d, 1H), 5.5-5.7(br, 1H), 6.6-6.8 (m, 5H), 7.1 (d, 2H); MS for C₂₄H₃₁N₃O₅ m/z 442.2[M+H].

Example 2B5 Preparation of Compound 801-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(3-methoxybenzyl)urea

¹H NMR (400 MHz, CDCl₃) δ=1.7 (s, 4H), 2.4-2.6 (m, 6H), 3.8 (s, 3H), 4.0(m, 1H), 4.1-4.2 (s, 6H), 4.8 (d, 1H), 5.1 (d, 1H), 5.2-5.4 (br, 1H),6.6-6.8 (m, 6H), 7.2 (dd, 1H); MS for C₂₄H₃₁N₃O₅ m/z 442.2 [M+H].

Example 2B6 Preparation of Compound 421-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(4-methylbenzyl)urea

¹H NMR (400 MHz, CDCl₃) δ=1.6 (s, 4H), 2.3 (s, 3H), 2.4-2.6 (m, 6H), 4.0(m, 1H), 4.2 (d, 2H), 4.21 (s, 4H), 4.7 (d, 1H), 5.2 (d, 1H), 5.4-5.6(br, 1H), 6.7-7.1 (m, 7H); MS (for C₂₄H₃₁N₃O₄ m/z 426.2 [M+H].

Example 2B7 Preparation of Compound 431-(4-chlorobenzyl)-3-(1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)urea

¹H NMR (400 MHz, CDCl₃) δ=1.7 (s, 4H), 2.5-2.7 (m, 6H), 4.0 (m, 1H), 4.2(s, 6H), 4.8 (d, 1H), 5.2 (d, 1H), 5.4-5.5 (br, 1H), 6.7-6.9 (m, 3H),7.1 (d, 2H), 7.3 (d, 2H); MS for C₂₃H₂₈N₃ClO₄ m/z 446 [M+H], 447.5[M+2].

Example 2B8 Preparation of Compound 101-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-((S)-1-phenylethyl)urea

¹H NMR (400 MHz, CDCl₃) δ=1.4 (d, 3H), 1.6 (s, 4H), 2.2-2.5 (m, 4H), 2.5(dd, 1H), 2.6 (dd, 1H), 3.9 (m, 1H), 4.2 (s, 4H), 4.5 (m, 1H), 4.8 (d,1H), 5.0 (d, 1H), 5.1-5.3 (br, 1H), 6.6-6.9 (m, 3H), 7.2-7.4 (m, 5H); MSfor C₂₄H₃₁N₃O₄ m/z 426.2 [M+H].

Example 2B9 Preparation of Compound 2861-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(®1-phenylethyl)urea

¹H NMR (400 MHz, CDCl₃) δ=1.3 (d, 3H), 1.7 (s, 4H), 2.2-2.6 (m, 6H), 3.9(m, 1H), 4.2 (s, 4H), 4.6-4.7 (m, 2H), 5.3 (d, 1H), 5.6-5.7 (br, 1H),6.6 (d, 1H), 6.7 (d, 1H), 6.8 (s, 1H), 7.2-7.4 (m, 5H); MS forC₂₄H₃₁N₃O₄ m/z 426.0 [M+H].

Example 2B10 Preparation of Compound 691-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(naphthalen-2-yl)urea

¹H NMR (400 MHz, CDCl₃) δ=1.6 (s, 4H), 2.4-2.8 (m, 6H), 4.1 (s, 5H), 4.8(s, 1H), 6.0 (d, 1H), 6.7 (s, 2H), 6.9 (s, 1H), 7.1-7.8 (m, 7H); MS forC₂₆H₂₉N₃O₄ m/z 448.1 [M+H].

Example 2B11 Preparation of Compound 2881-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(naphthalen-1-yl)urea

¹H NMR (400 MHz, CDCl₃) δ=1.6 (s, 4H), 2.4 (s, 4H), 2.6 (d, 2H), 4.1 (m,1H), 4.2 (s, 4H), 4.8 (d, 1H), 5.4 (d, 1H), 6.5 (d, 1H), 6.6 (d, 1H),6.7 (s, 1H), 7.2-7.6 (m, 3H), 7.7 (d, 1H), 7.8 (d, 1H), 8.0 (d, 1H); MSfor C₂₆H₂₉N₃O₄ m/z 448.1 [M+H].

Example 2B12 Preparation of Compound 711-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-((S)-1-(naphthalen-1-yl)ethyl)urea

¹H NMR (400 MHz, CDCl₃) δ=1.4 (s, 4H), 1.5 (d, 3H), 2.3 (s, 4H), 2.4(dd, 1H), 2.6 (dd, 1H), 3.9 (br, 1H), 4.2 (s, 4H), 4.7 (s, 1H), 5.0 (d,1H), 5.3 (br, 1H), 5.5 (br, 1H), 6.6 (m, 3H), 7.4-7.6 (m, 4H), 7.7 (d,1H), 7.8 (d, 1H), 8.1 (d, 1H); MS for C₂₈H₃₃N₃O₄ m/z 476.2 [M+H].

Example 2B13 Preparation of Compound 701-(biphenyl-4-yl)-3-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)urea

¹H NMR (400 MHz, CDCl₃) δ=1.7 (s, 4H), 2.6-2.8 (m, 6H), 4.1 (br, 1H),4.2 (s, 4H), 4.9 (br, 1H), 5.9 (d, 1H), 6.8 (s, 2H), 6.9 (s, 1H),7.2-7.6 (m, 9H); for C₂₈H₃₁N₃O₄ m/z 474.1 [M+H].

Example 2B14 Preparation of Compound 811-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(4-(trifluoromethyl)phenyl)urea

¹H NMR (400 MHz, CDCl₃) δ=1.7 (s, 4H), 2.4-2.7 (m, 6H), 4.0 (br, 1H),4.2 (s, 4H), 4.8 (br, 1H), 5.9 (br, 1H), 6.8 (s, 2H), 6.9 (s, 1H), 7.3(d, 2H), 7.5 (d, 2H); MS for C₂₃H₂₆F₃N₃O₄ m/z 465.97 [M+H].

Example 2B15 Preparation of Compound 681-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(3-(trifluoromethyl)phenyl)urea

¹H NMR (400 MHz, CDCl₃) δ=1.7 (s, 4H), 2.5-2.9 (m, 6H), 4.0 (br, 1H),4.2 (s, 4H), 4.8 (br, 1H), 5.9 (br, 1H), 6.8 (s, 2H), 6.9 (s, 1H),7.2-7.6 (m, 4H); MS for C₂₃H₂₆F₃N₃O₄ m/z 466.0 [M+H].

Example 2B16 Preparation of Compound 821-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(4-(trifluoromethoxy)phenyl)urea

¹H NMR (400 MHz, CDCl₃) δ=1.7 (s, 4H), 2.4-2.7 (m, 6H), 4.0 (br, 1H),4.2 (s, 4H), 4.8 (br, 1H), 5.9 (br, 1H), 6.8 (s, 2H), 6.9 (s, 1H), 7.0(d, 2H), 7.2 (d, 2H); MS for C₂₃H₂₆F₃N₃O₅ m/z 481.5 [M], 482.5 [M+H].

Example 2B17 Preparation of Compound 1331-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(4-(2-methylthiazol-4-yl)phenyl)urea

¹H NMR (400 MHz, CDCl₃) δ=1.7 (s, 4H), 2.4-2.7 (m, 6H), 2.7 (s, 3H), 4.1(br, 1H), 4.2 (s, 4H), 4.8 (br, 1H), 5.9 (d, 1H), 6.8 (s, 2H), 6.9 (s,1H), 7.2 (s, 1H), 7.3 (d, 2H), 7.7 (d, 2H); MS for C₂₆H₃₀N₄O₄S m/z 494.9[M+H].

Example 2B18 Preparation of Compound 71-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-dodecylurea

¹H NMR (400 MHz, CDCl₃) δ=0.9 (t, 3H), 1.3 (br, 18H), 1.4 (m, 2H), 1.8(s, 4H), 2.5-2.7 (m, 6H), 3.1 (q, 2H), 4.0 (m, 1H), 4.3 (s, 4H), 4.4(br, 1H), 4.76 (d, 1H), 4.8 (d, 1H), 6.7-6.8 (dd, 2H), 6.9 (s, 1H); MSfor C₂₈H₄₇N₃O₄ m/z 489.7 [M+H], 490.9 [M+2].

Example 2B19 Preparation of Compound 2871-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(2-(thiophen-2-yl)ethyl)urea

¹H NMR (400 MHz, CDCl₃) δ=1.7 (s, 4H), 2.5-2.7 (m, 6H), 3.0 (t, 2H), 3.8(q, 2H), 4.0 (m, 1H), 4.2 (s, 4H), 4.8 (d, 2H), 4.9 (d, 1H), 6.7-6.8 (m,3H), 6.9 (d, 1H), 6.9 (dd-1H), 7.1 (d, 1H); MS for C₂₂H₂₉N₃O4S m/z 432.1[M+H].

Example 2B20 Preparation of1-((1R,2R)-1-(4-(4-fluorobutoxy)phenyl)-1-hydroxy-3-((R)-3-hydroxypyrrolidin-1-yl)propan-2-yl)-3-(4-methoxybenzyl)urea2,2,2-trifluoroacetate

¹H NMR (400 MHz, CD₃OD) δ=1.8-2.2 (m, 6H), 3.2-3.3 (dd, 2H), 3.4-3.7 (m,3H), 3.8 (s, 3H), 3.82-4.1 (m, 4H), 4.3 (dd, 2H), 4.4 (dd, 1H), 4.5 (dd,2H), 4.8 (dd, 1H), 6.8 (d, 2H), 6.9 (d, 2H), 7 (m, 2H), 7.3 (d, 2H); MSfor C₂₆H₃₆FN₃O₅ m/z 491 [M+H].

Example 2B21 Preparation of1-(4-chlorobenzyl)-3-((1R,2R)-1-(4-(4-fluorobutoxy)phenyl)-1-hydroxy-3-((R)-3-hydroxypyrrolidin-1-yl)propan-2-yl)urea

¹H NMR (400 MHz, CDCl₃) δ=1.6-1.8 (m, 3H), 1.8-2 (m, 5H), 2-2.2 (m, 2H),2.2-2.3 (m, 2H), 2.8-2.4 (m, 5H), 2.9 (m, 1H), 3.9-4.0 (m, 3), 4.1-4.4(m, 3H), 4.5 (t, 1H), 4.6-4.7 (m, 1H), 4.75 (d, 1H), 6.8 (d, 2H), 7.1(d, 2H), 7.15-7.3 (m, 4H); MS for C₂₅H₃₃ClFN₃O₄ m/z 494 [M+H].

Example 3 GM3 Elisa Assay

B16-FO cells from ATCC (American Tissue Culture Collection) were grownin DMEM media (ATCC) with 10% Fetal Bovine Serum (Hyclone) andPen/Step/Glutamine (Biowhittaker). 4000 cells per well were plated oncollagen coated plates (BD) and allowed to attach for 6 hours in anincubator (37 degrees, 5% CO2). After 6 hours the compounds and controlswere added to the wells, the plates mixed and returned to the incubatorfor 2 days. Day of assay the cells were fixed for 20 minutes with 1%formaldehyde and then washed with Tris Buffered Saline (TBS) 3 times,150 μl of TBS was left in the wells and 50 μl of goat serum (Invitrogen)was added, the plates mixed and incubated for 1 hour at roomtemperature. The plates were flicked and the cells incubated with themonoclonal Antibody to GM3 (NeuAc) (Cosmo) for 45 minutes as roomtemperature. The plates were then washed 3 times with TBS, leaving 150μl of TBS in the wells and Peroxidase AffinPure F (ab′) 2 frag GtAnti-mouse IgM, μ Chain Specific (Jackson Immuno Research) was added in500, the plates mixed and incubated for 45 minutes at room temperature.The plates were washed 3 times with TBS, flicked and blotted and 100 μlof Quantablu (Pierce) was added to the wells and incubated for 1 hourthen read on a Fluorometer at Ex 325 and Em 420. The data was thenanalyzed using standard programs.

The results of the GM3 Elisa assay are summarized in Tables 1 and 2. InTables 1 and 2, IC50 values are indicated as “A,” “B,” “C,” “D,” and “E”for those of less than or equal to 0.1 μm; those of greater than 0.1 μm,and less than or equal to 1 μm; those of greater than 1 μm, and lessthan or equal to 3 μm; those of greater than 3 μm, and less than orequal to 10 μm; those of greater than 10 μm, respectively. As shown inTables 1, 2 and 3, numerous compounds of the invention were shown to beinhibitors of GM3.

TABLE 1 IC 50 Values from GM3 Elisa Assay Z—R* Compound IC50_uM_Mean

 1 B

 2 C

 3 C

 4 B

 5 B

 6 B

 7 A

 8 B

 9 B

 10 B

 11 A

 12 B

 13 B

 14 B

 15 B

 16 D

 17 A

 18 B

 19 B

 20 B

 21 A

 22 C

 23 A

 24 B

 25 B

 26 B

 27 A

 28 A

 29 A

 30 B

 31 B

 32 A

 33 A

 34 C

 35 C

 36 B

 37 B

 38 B

 39 A

 40 A

 41 A

 42 A

 43 A

 44 B

 45 B

 46 B

 47 B

 48 A

 49 A

 50 B

 51 B

 52 B

 53 C

 54 A

 55 A

 56 A

 57 A

 58 B

 59 A

 60 A

 61 A

 62 B

 63 A

 64 A

 65 A

 66 A

 67 A

 68 B

 69 B

 70 A

 71 B

 72 B

 73 A

 74 B

 75 B

 76 B

 77 A

 78 B

 79 A

 80 B

 81 B

 82 A

 83 A

 84 C

 85 A

 86 A

 87 A

 88 B

 89 B

 90 B

 91 B

 92 A

 93 A

 94 C

 95 A

 96 A

 97 B

 98 D

 99 B

100 A

101 A

102 C

103 A

104 B

105 B

106 B

107 D

108 B

109 A

110 A

111 B

112 B

113 B

114 B

115 A

116 B

117 B

118 B

119 A

120 B

121 D

122 D

123 C

124 C

125 B

126 D

127 B

128 C

129 B

130 C

131 A

132 D

133 D

134 C

135 C

136 A

137 A

138 A

139 A

140 A

141 A

142 A

143 A

144 A

145 B

146 B

147 B

148 A

149 B

150 C

151 B

152 A

153 B

154 B

155 B

156 A

157 A

158 A

159 A

160 B

161 B

162 A

163 A

164 A

165 A

166 A

167 A

168 A

169 A

170 B

171 C

172 B

173 A

174 A

175 A

176 A

177 B

178 A

179 A

180 B

181 A

182 B

183 A

184 B

185 B

186 A

187 B

188 B

189 B

190 A

191 A

192 B

193 B

194 B

195 B

196 C

197 A

198 B

199 A

200 B

201 C

202 B

203 A

204 B

205 A

206 B

207 A

208 B

209 A

210 B

211 B

212 D

213 B

214 D

215 B

216 A

217 A

218 D

219 D

220 B

221 A

222 A

223 A

224 B

225 A

226 D

227 C

228 B

229 E

230 B

231 A

232 C

233 C

234 B

235 B

236 A

237 A

238 A

239 D

240 C

241 A

291 C

292 C

293 B

294 B

295 A

296 B

297 C

298 B

299 A

300 A

301 A

302 A

303 A

304 A

305 A

306 B

307 A

308 A

TABLE 2 IC 50 Values from GM3 Elisa Assay Structure CompoundIC50_uM_Mean

242 D

243 A

244 A

245 D

246 C

247 A

248 B

249 C

250 B

251 B

252 B

253 B

254 B

255 C

256 B

257 D

258 D

259 A

260 A

261 B

262 A

263 B

264 A

265 A

266 A

267 A

268 A

269 A

270 A

271 A

272 A

273 B

274 C

275 A

276 B

277 D

278 E

279 C

282 C

283 A

284 A

285 A

286 D

287 C

289 B

309 A

310 C

311 C

312 B

313 A

314 C

315 B

316 D

317 B

318 B

319 B

320 A

321 C

322 B

TABLE 3 IC 50 Values Structure IC50_uM_Mean Compound

B 340

A 341

B 342

B 343

A 344

A 345

B 346

B 347

B 348

B 349

A 350

B 351

D 352

B 353

B 354

C 355

C 356

B 357

A 358

B 359

B 360

D 361

D 362

B 363

A 364

A 365

A 366

A 367

A 368

A 369

A 370

A 371

A 372

A 373

A 374

B 375

A 376

A 377

A 378

B 379

A 380

C 381

B 382

B 383

B 384

C 385

B 386

B 387

A 388

A 389

A 390

B 391

D 392

D 393

C 394

D 395

D 396

D 397

D 398

C 399

D 400

B 401

D 402

C 403

D 404

C 405

D 406

C 407

C 408

B 409

D 410

D 411

A 412

A 413

B 414

B 415

A 416

A 417

A 418

A 419

A 420

A 421

D 422

C 423

D 424

D 425

D 426

D 427

D 428

D 429

A 430

A 431

A 432

A 433

A 434

A 435

A 436

A 437

A 438

B 439

A 440

A 441

A 442

A 443

B 444

B 445

A 446

A 447

B 448

A 449

A 450

B 451

B 452

A 453

A 454

A 455

A 456

A 457

D 458

D 459

C 460

B 461

C 462

B 463

D 464

B 465

D 466

B 467

A 468

B 469

B 470

C 471

B 472

A 473

B 474

A 475

B 476

D 477

B 478

A 479

C 480

D 481

D 482

D 483

C 484

D 485

C 486

D 487

C 488

D 489

D 490

C 491

D 492

C 493

B 494

A 495

A 496

A 497

A 498

A 499

A 500

A 501

A 502

A 503

B 504

D 505

D 506

B 507

D 508

B 509

D 510

D 511

C 512

D 513

B 514

A 515

B 516

B 517

B 518

D 519

C 520

D 521

A 522

B 523

B 524

A 525

B 526

C 527

C 528

A 529

D 530

A 531

A 532

B 533

D 534

D 535

D 536

A 537

D 538

D 539

D 540

D 541

D 542

D 543

B 544

B 545

D 546

A 547

C 548

D 549

D 550

D 551

C 552

D 553

D 554

B 555

D 556

D 557

C 558

B 559

B 560

D 561

B 562

D 563

B 564

A 565

A 566

B 567

B 568

D 569

D 570

D 571

B 572

B 573

B 574

B 575

B 576

B 577

A 578

D 579

D 580

B 581

D 582

D 583

B 584

B 585

A 586

B 587

D 588

C 589

D 590

D 591

A 592

B 593

C 594

D 595

D 596

D 597

D 598

C 599

C 600

D 601

D 602

B 603

D 604

D 605

D 606

C 607

D 608

B 609

D 610

D 611

D 612

D 613

D 614

B 615

D 616

C 617

D 618

C 619

B 620

C 621

D 622

D 623

D 624

D 625

B 626

D 627

A 628

B 629

B 630

D 631

D 632

B 633

B 634

D 635

D 636

B 637

D 638

B 639

B 640

A 641

B 642

C 643

C 644

D 645

D 646

B 647

648

649

B 650

C 651

D 652

A 653

C 654

B 655

A 656

B 657

B 658

B 659

B 660

C 661

B 662

B 663

C 664

D 665

B 666

B 667

C 668

D 669

D 670

D 671

D 672

D 673

D 674

D 675

D 676

D 677

D 678

D 679

A 680

C 681

D 682

D 683

B 684

D 685

D 686

D 687

D 688

D 689

A 690

D 691

B 692

A 693

B 694

B 695

C 696

B 697

B 698

A 699

B 700

C 701

A 702

A 703

A 704

A 705

A 706

A 707

A 708

A 709

A 710

A 711

B 712

B 713

D 714

D 715

D 716

D 717

D 718

D 719

D 720

D 721

A 722

A 723

B 724

B 725

B 726

A 727

A 728

A 729

A 730

A 731

B 732

A 733

A 734

A 735

A 736

B 737

A 738

A 739

A 740

A 741

What is claimed is:
 1. A compound represented by the followingstructural formula:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is a phenylgroup optionally substituted with one or more substituents selected fromhalogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, —OR³⁰, —SR³⁰,—N(R³¹)₂, Ar¹, —V_(o)—OR³⁰, —V_(o)—N(R³¹)₂, —V_(o)—Ar¹, —O—V_(o)—Ar¹,—O—V₁—N(R³¹)₂, —S—V_(o)—Ar¹, —S—V₁—N(R³¹)₂, —N(R³¹)—V_(o)—Ar¹,—N(R³¹)—V₁—N(R³¹)₂, —O—[CH₂]_(p)—O—, —S—[CH₂]_(p)—S— or —[CH₂]_(q)—; Ar¹is a phenyl group each optionally substituted with one or moresubstituents selected from halogen, C1-C6 alkyl, amino, C1-C6alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy,C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl or C1-C6haloalkyl; and each R³⁰ is independently i) hydrogen; ii) a phenyl groupoptionally substituted with one or more substituents selected fromhalogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl,C1-C6 alkylcarbonyl or C1-C6 haloalkyl; or iii) an C1-C10 alkyl groupoptionally substituted with one or more substituents selected fromhalogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy,nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6alkylcarbonyl or C1-C6 haloalkyl; and each R³¹ is independently R³⁰, or—N(R³¹)₂ is an optionally substituted non-aromatic heterocyclic group;—N(R²R³) is a pyrrolidinyl group optionally substituted with one or moresubstituents selected from halogen, alkyl, haloalkyl, —OR⁴⁰,—O(haloalkyl), —SR⁴⁰, —NO₂, —CN, —N(R⁴¹)₂, —NR⁴¹C(O)R⁴⁰, —NR⁴¹C(O)OR⁴²,—N(R⁴¹)C(O)N(R⁴¹)₂, —C(O)R⁴⁰, —C(S)R⁴⁰, —C(O)OR⁴⁰, —OC(O)R⁴⁰,—C(O)N(R⁴¹)₂, —S(O)₂R⁴⁰, —SO₂N(R⁴¹)₂, —S(O)R⁴², —SO₃R⁴⁰, Ar², V₂—Ar²,—V₂—OR⁴⁰, —V₂—O(haloalkyl), —V₂—SR⁴⁰, —V₂—NO₂, —V₂—CN, —V₂—N(R⁴¹)₂,—V₂—NR⁴¹C(O)R⁴⁰, —V₂—NR⁴¹CO₂R⁴², —V₂—N(R⁴¹)C(O)N(R⁴¹)₂, —V₂—C(O)R⁴⁰,—V₂—C(S)R⁴⁰, —V₂—CO₂R⁴⁰, —V₂—OC(O)R⁴⁰, —V₂—C(O)N(R⁴¹)₂—, —V₂—S(O)₂R⁴⁰,—V₂—SO₂N(R⁴¹)₂, —V₂—S(O)R⁴², —V₂—SO₃R⁴⁰, —O—V₂—Ar² or —S—V₂—Ar²; each V₂is independently a C1-C4 alkylene group; Ar² is an aryl group eachoptionally substituted with one or more substituents selected fromhalogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl,C1-C6 alkylcarbonyl or C1-C6 haloalkyl; and each R⁴⁰ is independently i)hydrogen; ii) an aryl group optionally substituted with one or moresubstituents selected from halogen, C1-C6 alkyl, amino, C1-C6alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy,C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl or C1-C6haloalkyl; or iii) an C1-C10 alkyl group optionally substituted with oneor more substituents selected from halogen, amino, C1-C6 alkylamino,C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl or C1-C6haloalkyl; and each R⁴¹ is independently R⁴⁰, —CO₂R⁴⁰, —SO₂R⁴⁰ or—C(O)R⁴⁰; or —N(R⁴¹)₂ taken together is an optionally substitutednon-aromatic heterocyclic group; and each R⁴² is independently: i) anaryl group optionally substituted with one or more substituents selectedfrom halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino,C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6alkoxycarbonyl, C1-C6 alkylcarbonyl or C1-C6 haloalkyl; or ii) an C1-C10alkyl group optionally substituted with one or more substituentsselected from halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino,C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6alkoxycarbonyl, C1-C6 alkylcarbonyl or C1-C6 haloalkyl; R⁴ is analiphatic group or an aryl group optionally substituted with one or moresubstituents selected from halogen, alkyl, haloalkyl, Ar³, Ar³—Ar³,—OR⁵⁰, —O(haloalkyl), —SR⁵⁰, —NO₂, —CN, —NCS, —N(R⁵¹)₂, —NR⁵¹C(O)R⁵⁰,—NR⁵¹C(O)OR⁵², —N(R⁵¹)C(O)N(R⁵¹)₂, —C(O)R⁵⁰, —C(S)R⁵⁰, —C(O)OR⁵⁰,—OC(O)R⁵⁰, —C(O)N(R⁵¹)₂, —S(O)₂R⁵⁰, —SO₂N(R⁵¹)₂, —S(O)R⁵², —SO₃R⁵⁰,—NR⁵¹SO₂N(R⁵¹)₂, —NR⁵¹SO₂R⁵², —V₄—Ar³, —V—OR⁵⁰, —V₄—O(haloalkyl),—V₄—SR⁵⁰, —V₄—NO₂, —V₄—CN, —V₄—N(R⁵¹)₂, —V₄—NR⁵¹C(O)R⁵⁰, —V₄—NR⁵¹CO₂R⁵²,—V₄—N(R⁵¹)C(O)N(R⁵¹)₂, —V₄—C(O)R⁵⁰, —V₄—C(S)R⁵⁰, —V₄—CO₂R⁵⁰,—V₄—OC(O)R⁵⁰, —V₄—C(O)N(R⁵¹)₂—, —V₄—S(O)₂R⁵⁰, —V₄—SO₂N(R⁵¹)₂,—V₄—S(O)R⁵², —V₄—SO₃R⁵⁰, —V₄—NR⁵¹SO₂N(R⁵¹)₂, —V₄—NR⁵¹SO₂R⁵², —O—V₄—Ar³,—O—V₅—N(R⁵¹)₂, —S—V₄—Ar³, —S—V₅—N(R⁵¹)₂, —N(R⁵¹)—V₄—Ar³,—N(R⁵¹)—V₅—N(R⁵¹)₂, —NR⁵¹C(O)—V₄—N(R⁵¹)₂, —NR⁵¹C(O)—V₄—Ar³,—C(O)—V₄—N(R⁵¹)₂, —C(O)—V₄—Ar³, —C(S)—V₄—N(R⁵¹)₂, —C(S)—V₄—Ar³,—C(O)O—V₅—N(R⁵¹)₂, —C(O)O—V₄—Ar³, —O—C(O)—V₅—N(R⁵¹)₂, —O—C(O)—V₄—Ar³,—C(O)N(R⁵¹)—V₅—N(R⁵¹)₂, —C(O)N(R⁵¹)—V₄—Ar³, —S(O)₂—V₄—N(R⁵¹)₂,—S(O)₂—V₄—Ar³, —SO₂N(R⁵¹)—V₅—N(R⁵¹)₂, —SO₂N(R⁵¹)—V₄—Ar³,—S(O)—V₄—N(R⁵¹)₂, —S(O)—V₄—Ar³, —S(O)₂—O—V₅—N(R⁵¹)₂, —S(O)₂—O—V₄—Ar³,—NR⁵¹SO₂—V₄—N(R⁵¹)₂, —NR⁵¹SO₂—V₄—Ar³, —O—[CH₂]_(p′)—O—,—S—[CH₂]_(p′)—S—, or —[CH₂]_(q′)—; each V₄ is independently a C1-C10alkylene group; each V₅ is independently a C2-C10 alkylene group; eachAr³ is independently an aryl group each optionally substituted with oneor more substituents selected from halogen, alkyl, amino, alkylamino,dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy or haloalkyl;and each R⁵⁰ is independently i) hydrogen; ii) an aryl group optionallysubstituted with one or more substituents selected from halogen, alkyl,amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy,haloalkoxy, alkoxycarbonyl, alkylcarbonyl or haloalkyl; or iii) an alkylgroup optionally substituted with one or more substituents selected fromhalogen, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy,haloalkoxy, alkoxycarbonyl, alkylcarbonyl or haloalkyl; and each R⁵¹ isindependently R⁵⁰, —CO₂R⁵⁰, —SO₂R⁵⁰ or —C(O)R⁵⁰; or —N(R⁵¹)₂ takentogether is an optionally substituted non-aromatic heterocyclic group;and each R⁵² is independently: i) an aryl group optionally substitutedwith one or two substituents selected from halogen, alkyl, amino,alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy,alkoxycarbonyl, alkylcarbonyl or haloalkyl; or ii) an alkyl groupoptionally substituted with one or more substituents selected fromhalogen, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy,haloalkoxy, alkoxycarbonyl, alkylcarbonyl or haloalkyl; and each p′ is1, 2, 3 or 4; and each q′ is 3, 4, 5 or 6; and R⁷ is —H or C1-C6 alkyl.2. The compound of claim 1, wherein —N(R²R³) is a pyrrolidinyl groupoptionally substituted with one or more substituents selected fromhalogen, C1-C5 alkyl, C1-C5 haloalkyl, hydroxyl, C1-C5 alkoxy, nitro,cyano, C1-C5 alkoxycarbonyl, C1-C5 alkylcarbonyl or C1-C5 haloalkoxy,amino, C1-C5 alkylamino or C1-C5 dialkylamino.
 3. The compound of claim2, represented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein: R⁸ is —H, or anaryl or C1-C6 alkyl group each optionally and independently substitutedwith one or more substituents selected from halogen, C1-C10 alkyl,C1-C10 haloalkyl, Ar³, —OR⁵⁰, —O(haloalkyl), —SR⁵⁰, —NO₂, —CN, —N(R⁵¹)₂,—NR⁵¹C(O)R⁵⁰, —C(O)R⁵⁰, —C(O)OR⁵⁰, —OC(O)R⁵⁰, —C(O)N(R⁵¹)₂, —V₄—Ar³,—V—OR⁵⁰, —V₄—O(haloalkyl), —V₄—SR⁵⁰, —V₄—NO₂, —V₄—CN, —V₄—N(R⁵¹)₂,—V₄—NR⁵¹C(O)R⁵⁰, —V₄—C(O)R⁵⁰, —V₄—CO₂R⁵⁰, —V₄—OC(O)R⁵⁰,—V₄—C(O)N(R⁵¹)₂—, —O—V₄—Ar³, —O—V₅—N(R⁵¹)₂, —S—V₄—Ar³, —S—V₅—N(R⁵¹)₂,—N(R⁵¹)—V₄—Ar³, —N(R⁵¹)—V₅—N(R⁵¹)₂, —NR⁵¹C(O)—V₄—N(R⁵¹)₂,—NR⁵¹C(O)—V₄—Ar³, —C(O)—V₄—N(R⁵¹)₂, —C(O)—V₄—Ar³, —C(O)O—V₅—N(R⁵¹)₂,—C(O)O—V₄—Ar³, —O—C(O)—V₅—N(R⁵¹)₂, —O—C(O)—V₄—Ar³,—C(O)N(R⁵¹)—V₅—N(R⁵¹)₂, —C(O)N(R⁵¹)—V₄—Ar³, —O—[CH₂]_(p′)—O— or—[CH₂]_(q′)—; and k is 0, 1, 2, 3, 4, 5 or
 6. 4. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and thecompound of claim 1, or a pharmaceutically acceptable salt thereof.
 5. Amethod of treating a subject having type 2 diabetes, comprisingadministering to the subject a therapeutically effective amount of thecompound of claim 1, or a pharmaceutically acceptable salt thereof.
 6. Amethod of treating a subject having renal hypertrophy or hyperplasiaassociated with diabetic nephropathy, comprising administering to thesubject a therapeutically effective amount of the compound of claim 1,or a pharmaceutically acceptable salt thereof.
 7. A method of decreasingplasma TNF-α in a subject in need thereof, comprising administering tothe subject a therapeutically effective amount of the compound of claim1, or a pharmaceutically acceptable salt thereof.
 8. A method oflowering blood glucose levels in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of thecompound of claim 1, or a pharmaceutically acceptable salt thereof.
 9. Amethod of decreasing glycated hemoglobin levels in a subject in needthereof, comprising administering to the subject a therapeuticallyeffective amount of the compound of claim 1, or a pharmaceuticallyacceptable salt thereof.
 10. A method of inhibiting glucosylceramidesynthase or lowering glycosphingolipid concentrations in a subject inneed thereof, comprising administering to the subject a therapeuticallyeffective amount of the compound of claim 1, or a pharmaceuticallyacceptable salt thereof.
 11. A method of treating a subject withTay-Sachs, Gaucher's or Fabry's disease, comprising administering to thesubject a therapeutically effective amount of the compound of claim 1,or a pharmaceutically acceptable salt thereof.
 12. The compound of claim1, wherein the compound is a (1R,2R) stereoisomer.
 13. The compound ofclaim 2, wherein R⁷ is —H, and R⁴ is an optionally substituted aryl orarylalkyl group.
 14. The compound of claim 13, wherein R⁴ is an aryl orarylalkyl group each optionally and independently substituted with oneor more substituents selected from halogen, C1-C10 alkyl, C1-C10haloalkyl, Ar³, —OR⁵⁰, —O(haloalkyl), —SR⁵⁰, —NO₂, —CN, —N(R⁵¹)₂,—NR⁵¹C(O)R⁵⁰, —C(O)R⁵⁰, —C(O)OR⁵⁰, —OC(O)R⁵⁰, —C(O)N(R⁵¹)₂, —V₄—Ar³,—V—OR⁵⁰, —V₄—O(haloalkyl), —V₄—SR⁵⁰, —V₄—NO₂, —V₄—CN, —V₄—N(R⁵¹)₂,—V₄—NR⁵¹C(O)R⁵⁰, —V₄—C(O)R⁵⁰, —V₄—CO₂R⁵⁰, —V₄—OC(O)R⁵⁰,—V₄—C(O)N(R⁵¹)₂—, —O—V₄—Ar³, —O—V₅—N(R⁵¹)₂, —S—V₄—Ar³, —S—V₅—N(R⁵¹)₂,—N(R⁵¹)—V₄—Ar³, —N(R⁵¹)—V₅—N(R⁵¹)₂, —NR⁵¹C(O)—V₄—N(R⁵¹)₂,—NR⁵¹C(O)—V₄—Ar³, —C(O)—V₄—N(R⁵¹)₂, —C(O)—V₄—Ar³, —C(O)O—V₅—N(R⁵¹)₂,—C(O)O—V₄—Ar³, —O—C(O)—V₅—N(R⁵¹)₂, —O—C(O)—V₄—Ar³,—C(O)N(R⁵¹)—V₅—N(R⁵¹)₂, —C(O)N(R⁵¹)—V₄—Ar³, —O—[CH₂]_(p′)—O— or—[CH₂]_(q′)—, wherein arylalkyl includes straight and branched saturatedchains containing one to six carbon atoms.
 15. The compound of claim 3,wherein R⁸ is selected from:

wherein: each of rings A-Z5 is optionally substituted.
 16. The compoundof claim 15, wherein —N(R²R³) is an unsubstituted pyrrolidinyl group.17. The compound of claim 16, wherein each of rings A-Z5 is optionallysubstituted with one or more substituents selected from halogen, cyano,nitro, C1-C10 alkyl, C1-C10 haloalkyl, amino, C1-C10 alkylamino, C1-C10dialkylamino, aryl, aryloxy, hydroxy, C1-10 alkoxy, —O—[CH₂]_(p)—O— or—[CH₂]_(q)—.
 18. The compound of claim 17, wherein: —N(R²R³) ispyrrolidinyl; and the phenyl group represented by R¹ is optionallysubstituted with one or more substituents selected from —OH, —OCH₃,—OC₂H₅ or —O—[CH₂]_(p)—O—.
 19. The compound of claim 1, represented byone of the following structural formulas:

or a pharmaceutically acceptable salt of any of the foregoing.